- Email: [email protected]
Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation
Journal Pre-proof Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and rivaroxaban in atrial fibrillation
M. Jansson, S. Själander, V. Sjögren, H. Renlund, B. Norrving, A. Själander PII:
S0049-3848(19)30496-7
DOI:
https://doi.org/10.1016/j.thromres.2019.11.010
Reference:
TR 7514
To appear in:
Thrombosis Research
Received date:
6 April 2019
Revised date:
1 November 2019
Accepted date:
11 November 2019
Please cite this article as: M. Jansson, S. Själander, V. Sjögren, et al., Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and rivaroxaban in atrial fibrillation, Thrombosis Research (2019), https://doi.org/10.1016/ j.thromres.2019.11.010
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© 2019 Published by Elsevier.
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Direct Comparisons of Effectiveness and Safety of Treatment with Apixaban, Dabigatran and Rivaroxaban in Atrial Fibrillation Jansson M, MD 1*; Själander S, MD, PhD1; Sjögren V, MD, PhD1; Renlund H, PhD2; Norrving B, MD, PhD3, Själander A, MD, PhD1
1Department
of Public Health and Clinical Medicine, Umeå University, Sundsvall, Sweden; Clinical Research Center, Uppsala University, Uppsala, Sweden 3Department of Clinical Sciences Lund, Neurology, Skåne University Hospital, Lund University, Lund, Sweden
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*Correspondence:
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2Uppsala
Martin Jansson, MD Cardiology department Sundsvall Hospital 856 43 Sundsvall Sweden
Phone: +46768144039 Email: [email protected]
Manuscript word count: 2931
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Highlights Direct oral anticoagulant (DOAC) treatment prevents embolism in atrial fibrillation patients
Effectiveness and safety discrepancies among different DOACs are not well understood
Standard dose apixaban and dabigatran carries lower bleeding risk than rivaroxaban
Reduced dose apixaban carries lower bleeding risk than rivaroxaban and dabigatran
No statistically significant differences in effectiveness were found
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Abstract Introduction: Direct oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran. Materials and methods: Patients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015.
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Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC
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and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched
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using full optimal matching and directly compared.
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Results: A total of 25,843 NVAF patients were included. Patients treated with standard dose
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apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54-0.88) and HR 0.64 (95% CI 0.48-0.87). Regarding reduced dose, patients
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treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44-0.88) and HR 0.45 (95% CI 0.33-0.61). In reduced dose,
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patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found.
Conclusions: In this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.
Keywords Dabigatran, Rivaroxaban, Treatment Outcome, Apixaban, Anticoagulants, Atrial Fibrillation
Abbreviations DOACs (direct oral anticoagulants), NVAF (non-valvular atrial fibrillation), AF (atrial fibrillation), VKAs (vitamin K antagonists), OAC (oral anticoagulant), NPR (National Patient
Journal Pre-proof Registry), PPV (positive predictive value), ATC (Anatomic Therapeutic Chemical) SAH (subarachnoid hemorrhage), ICH (intracerebral hemorrhage)
Background Atrial fibrillation (AF) is the most common cardiac arrhythmia (1). A retrospective registry study with data from the Swedish Patient Register determined the Swedish adult prevalence of AF to be 2.9%, undiagnosed atrial fibrillation excluded, as well as atrial fibrillation treated in primary care only (2). Additionally, the overall prevalence of AF is increasing continuously, partly due to enhanced surveillance (3). AF is an independent risk factor for stroke, increasing
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stroke risk by near fivefold (1, 4). Furthermore, AF in patients with ischemic stroke is associated
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with higher mortality (5).
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Vitamin K antagonists (VKAs), e.g. warfarin, have been the standard of care for anticoagulation in patients with AF for the last 50 years (6). Anticoagulation with warfarin in
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patients with non-valvular atrial fibrillation (NVAF) reduces the stroke risk by two-thirds (7).
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Oral anticoagulant (OAC) therapy is superior to placebo and aspirin in reduction of stroke risk (8, 9). Even though OAC therapy using warfarin increases the risk of hemorrhagic stroke (10),
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reduction of ischemic stroke risk outweighs the risk of bleeding on OAC therapy (11). This is
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true even for patients who are frail, elderly, and have frequent falls (12, 13). Currently, stroke risk stratification in patients with AF is done using the CHA2DS2-VASc risk score (congestive heart failure (1p), hypertension (1p), age ≥75 years (2p), diabetes mellitus (1p), previous stroke/TIA (2p), vascular disease (1p), age 65-74 years (1p), sex category (female equals 1p)) (14). The European Society of Cardiology (ESC) recommends OAC in men with CHA2DS2-VASc ≥2p and women with ≥3p. Furthermore, treatment might be considered in men ≥1p and women with ≥2p (15). American College of Cardiology/American Heart Association recommend treatment in patients with CHA2DS2-VASc ≥2p (16) Vitamin K antagonists have several limitations including genetic variations in metabolism, various drug and food interactions and inertia in action onset and offset (6, 17, 18). Also, active cancer, dementia, major depression, chronic liver disease, poverty, longer distance to care and
Journal Pre-proof frequent hospitalizations influence quality of treatment (19, 20). Underuse of OAC therapy is common (21). Concerns of patient compliance, issues in monitoring and the need for doseadjusting VKA therapy are common reasons for withholding therapy (22). The many limitations of warfarin resulted in development of direct oral anticoagulants (DOACs). DOACs, including dabigatran, rivaroxaban, apixaban and edoxaban, are superior or non-inferior to warfarin in stroke prevention as well as having similar or lower risk of bleeding, as concluded in pivotal studies and subsequent observational studies (23-28).
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There are no direct comparisons of DOACs in randomized prospective trials. Previous
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comparisons of real-world data suggest that while rivaroxaban, dabigatran and apixaban have
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similar treatment effect regarding the risk of ischemic stroke, apixaban may be associated with a
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lower risk of major bleeding compared with the other two. (29-37). Our objective was to investigate whether effectiveness and safety differs among apixaban,
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rivaroxaban and dabigatran in direct pairwise comparisons in Sweden.
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Method The study was approved by the Ethics Review Board in Umeå (2015/142-31). The population of this study was identified from the Swedish anticoagulation quality registry Auricula. Auricula was launched in 2006 and contains information regarding OAC therapy in about 135 000 patients treated with either warfarin or DOAC. Information includes start and stop dates for treatment, indication for OAC treatment, INR values of patients on warfarin, prescribed dosage and creatinine levels in patients on DOAC. The register is continuously growing and includes both outpatient- and inpatient diagnoses of AF. It is used in a majority of
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Sweden´s healthcare regions, and where it is used, all anticoagulation treatments are registered
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in Auricula, with data on almost half of the Swedish patients with ongoing DOAC treatment at the
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time of data extraction. NVAF patients who were registered in Auricula and started on a new treatment period with dabigatran, rivaroxaban or apixaban between January 1, 2013, and
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December 31, 2015 were included. Patients with ongoing OAC treatment at January 1, 2013,
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were excluded. However, a previous period with OAC therapy was allowed. Patients with
indication valvular atrial fibrillation were excluded (Fig 1). New treatment was defined as a
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patient that was instituted on a DOAC for the first time. A switch from one DOAC to another was
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not allowed, but a patient could previously have been on Vitamin K antagonist. The study used an “as-treated” exposure definition considering the whole treatment period, short drug discontinuations were allowed.
Previous medical illnesses and most events during follow up (endpoints) were retrieved from the National Patient Registry (NPR), a Swedish health care administrative registry founded in 1964 and managed by the Swedish National Board of Health and Welfare. Co-morbidities and past medical event history were identified using ICD-10 (International Classification of Diseases 10th edition) codes. The NPR contains information from specialized inpatient and outpatient care. The degree of coverage is close to 100 % regarding inpatient care. Only 0.8 % of discharged patients are missing an ICD-10 code as main diagnosis, and external validation of the NPR has concluded a positive predictive value (PPV) of a diagnosis as high as 85-95% (38). PPV of the
Journal Pre-proof diagnosis atrial fibrillation is 97% (39). ICD-10-codes used in medical history are listed in Table 1, Appendix. Date of death of deceased persons was collected from the Swedish Cause of Death registry. The Swedish Stroke Register (Riksstroke), the national quality registry of stroke care in Sweden, was used for identification of events of intracerebral hemorrhage and ischemic stroke during the study period. This is motivated by higher validity for stroke diagnoses than the NPR. Also, it is possible for the same index stroke to be registered twice in the NPR. Coverage of
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Riksstroke was estimated to be 89 % in 2017 and has been stable during the time period of the
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study (40).
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Information concerning concurrent medication was retrieved from the Swedish Dispensed
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Drugs Registry using ATC (Anatomic Therapeutic Chemical) codes. The registry is managed by
compulsory for all pharmacies.
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the National Board of Health and Welfare and has complete coverage since reporting is
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Outcome events (endpoints) were ischemic stroke, all-cause stroke and systemic embolism, myocardial infarction, all-cause mortality, hemorrhagic stroke, or major bleeding that
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was fatal or required hospital care. Blood transfusion was not counted as a major bleeding event, due to lack of information on number of transfusions in the ICD10 codes. Death was identified in the Cause of Death registry while ischemic stroke and intracerebral hemorrhage were identified in Riksstroke. Remaining outcome events were extracted from the NPR. Hemorrhagic stroke was defined as either subarachnoid hemorrhage (SAH), retrieved from the NPR, or intracerebral hemorrhage (ICH). ICH was by itself an endpoint while also being included in all-cause stroke, intracranial bleeding, hemorrhagic stroke, and major bleeding. Every patient could be registered with up to three types of bleeding; gastrointestinal, intracranial (including ICH, SAH, subdural and epidural bleeding) and/or other bleeding. Only the first occurrence of each type of endpoint was included in the analyses.
Journal Pre-proof In short, all outcomes that were fatal or required specialist care, as well as stroke of any severity, were registered and analyzed. ICD-10-codes used in identification of outcomes are listed in Table 2, Appendix. 2.1 Statistical methods Full optimal matching was used in statistical analysis. An optimal matching between two groups creates clusters of individuals from both groups such that some metric is minimized globally. A full matching does not discard any individuals. Using the R package optmatch we created full
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optimal matchings between apixaban and rivaroxaban, rivaroxaban and dabigatran and
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dabigatran and apixaban, all based on the Mahalanobis distance between a set of matching covariates (Table 2) (41). We combined these to get the study population partitioned into
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clusters containing individuals from all three groups, with a weighting such that each cluster
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was balanced, and the total weight equaled the study population size. In this way the weighted
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groups look more similar in baseline covariates, and any parametric analysis is less vulnerable to model misspecification (42). Outcomes were analyzed via adjusted and weighted Cox
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regression, with standard errors from robust (sandwich) estimators.
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Results 3.1 Cohort description In total, the study included 25,843 NVAF patients. Of these, 11,493 were treated with apixaban, 6,453 with dabigatran and 7,897 with rivaroxaban. Baseline patient characteristics of the unmatched study sample are presented in Table 1. The mean patient age in the apixaban group was 75 years, in the dabigatran group 70 years and in the rivaroxaban group 74 years. In the apixaban group, 55.3% were male, with corresponding figures of 61.5% and 56.2% in the dabigatran and rivaroxaban groups, respectively. The median CHA2DS2VASc score was 2 for
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dabigatran, and 3 for the apixaban and rivaroxaban groups. After matching, there were no
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significant differences in baseline patient characteristics between apixaban vs dabigatran,
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apixaban vs rivaroxaban and dabigatran vs. rivaroxaban. Baseline patient characteristics of the matched cohorts are presented in Table 2. The mean patient age in the matched apixaban and
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rivaroxaban groups was 73.5 years, while in the matched dabigatran group 72.3 years. The
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matched apixaban and rivaroxaban groups had 57% male gender, compared to 58% in the
3.2 Primary outcomes
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matched dabigatran group.
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After matching, there were no significant differences in rates of all cause stroke and systemic embolism between the three DOACs. There were also no significant differences in ischemic stroke rates (Fig 2, Fig 3). Event rates of primary outcomes are presented in Table 3. Apixaban vs dabigatran There were no statistically significant differences in primary outcomes when comparing apixaban and dabigatran in standard dose. In reduced dose, apixaban treatment carried lower risk of major bleeding and gastrointestinal bleeding, HR 0.62 (95% CI 0.44-0.88) and HR 0.42 (95% CI 0.24-0.70). However, dabigatran treatment carried lower risk of all-cause mortality, HR 1,14 (95% CI 1.10-1.80) (Fig 2). Apixaban vs rivaroxaban
Journal Pre-proof In standard dose, apixaban treatment carried lower risk of major bleeding and gastrointestinal bleeding, HR 0.69 (95% CI 0.54-0.88) and HR 0.57 (95% CI 0.38-0.86). Also, apixaban treatment carried a lower risk of other bleeding, HR 0.70 (95% CI 0.51-0.96). In reduced dose, apixaban treatment carried a lower risk of hemorrhagic stroke and major bleeding, HR 0.36 (95% CI 0.130.99) and HR 0.45 (95% CI 0.33-0.61). Further considering reduced dose, apixaban treatment carried a lower risk of intracranial bleeding, gastrointestinal bleeding and other bleeding with HR 0.41 (95% CI 0.21-0.80), HR 0.51 (95% CI 0.32-0.80) and HR 0.42 (95% CI 0.25-0.63)
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respectively.
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Dabigatran vs rivaroxaban
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In standard dose, dabigatran treatment carried lower risk of major bleeding and other bleeding, HR 0.64 (95% CI 0.46-0.87) and HR 0.61 (95% CI 0.40-0.92). In reduced dose, dabigatran
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0.86) and HR 0.68 (95% CI 0.52-0.89).
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treatment carried a lower risk of other bleeding and all-cause mortality, HR 0.56 (95% CI 0.36-
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Discussion This study was designed to investigate differences in effectiveness and safety associated with different DOACs through matched and adjusted analyses in a setting of high-quality anticoagulation (27). In this cohort study, real-world data show a lower risk of major bleeding among NVAF patients treated with standard dose apixaban or dabigatran than those treated with rivaroxaban. When comparing type of bleeding, patients treated with apixaban have lower risk of gastrointestinal and other bleeding compared to patients treated with rivaroxaban.
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Patients treated with standard dose dabigatran have lower risk of other bleeding compared to patients treated with rivaroxaban. The study could not show any statistically significant
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difference in risk of major bleeding when comparing apixaban and dabigatran. Data in this study
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also show a lower risk of major bleeding among NVAF patients treated with reduced dose
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apixaban than for those treated with reduced dose dabigatran or rivaroxaban. When comparing type of bleeding, patients treated with reduced dose apixaban have lower risk of hemorrhagic
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stroke, intracranial bleeding, gastrointestinal bleeding and other bleedings than patients treated with reduced dose rivaroxaban, while only the risk of gastrointestinal bleeding is lower
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compared to patients treated with reduced dose dabigatran. Furthermore, patients treated with
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reduced dose dabigatran have lower risk of other bleeding compared to patients treated with reduced dose rivaroxaban. Also, patients treated with reduced dose dabigatran have lower allcause mortality than patients treated with reduced dose apixaban or rivaroxaban. We found no statistically significant differences in effectiveness considering all-cause stroke and systemic embolism. Previous findings through clinical trials and meta-analyses conclude DOACs as superior or non-inferior to warfarin in prevention of stroke and systemic embolism as well as having similar or lower risk of bleeding (23-25, 43-48). Recent observational studies comparing DOACs vs. warfarin have reproduced these findings (27-29, 49-51). In addition, observational studies and meta-analyses comparing DOACs vs. warfarin indicate a lower risk of major bleeding with use of dabigatran and apixaban compared with use of rivaroxaban (47, 51-54). Also,
Journal Pre-proof previous studies comparing effectiveness and safety of individual DOAC without using warfarin as indirect comparator (31, 36, 37, 55, 56). One US study compared rivaroxaban and dabigatran treatment among elderly with NVAF. The study was restricted to anticoagulant naive patients and only standard-dose regimes were compared. Dabigatran was associated with decreased risk of major bleeding compared to rivaroxaban (55). In addition, two other US administrative claims database studies have investigated safety and effectiveness among NVAF patients on dabigatran, rivaroxaban or apixaban and show decreased risk of major bleeding associated with both
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dabigatran and apixaban compared to rivaroxaban (31, 56). However, patients with previous
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use of other anticoagulants were included and no distinction was made between dosing regimens (31, 56). Also, a recent Danish study showed no statistical significance in either risk of
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stroke and systemic embolism or risk of major bleeding when directly comparing rivaroxaban,
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dabigatran and apixaban in propensity score matched cohorts, thus, not replicating previous findings. However, matching used the nearest neighbor algorithm, and only patients with
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standard dosing were studied, which could partly explain why their results differs from ours
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(36). Also, a previous meta-analysis of real-world data suggest that while rivaroxaban, dabigatran and apixaban have similar treatment effect regarding the risk of ischemic stroke,
(37).
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apixaban may be associated with a lower risk of major bleeding compared with the other two.
The results of our study confirm previous findings, showing no statistically significant difference in prevention of stroke or systemic embolism and a favorable bleeding risk profile for apixaban and dabigatran vs. rivaroxaban. This could either be due to actual differences in bleeding risk between these DOACs, or a propensity for the clinicians to choose rivaroxaban due to the once daily dosing regime in patients with perceived worse compliance. Likewise, the lower all-cause mortality seen in patients on low-dose dabigatran might be due to confounding by indication that remains despite the matching procedure. To our knowledge, our study is the first to directly compare (without warfarin as indirect comparator) both standard and reduced dose regimes of apixaban, dabigatran and rivaroxaban among anticoagulant naive
Journal Pre-proof patients in a full optimal matching design, showing statistically significant differences in safety among individual DOAC. With current recommendations of DOACs as first-line anticoagulant therapy for NVAF patients, this study contributes new findings from a clinical practice setting concerning individual risks and benefits associated with different DOACs in direct comparison (14). 4.1 Limitations The main limitation of this study is the non-randomized, retrospective design, not allowing for
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causal relationship between treatment and outcome being established. Also, although patients
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picked up their prescribed medication from a pharmacy, this does not mean that the medication was taken as prescribed. Diagnosis codes may be incorrectly coded, and may not be indicative of
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disease. Furthermore, some diagnoses are probably missing since there is no data on diagnoses
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from primary health care. However, a previous investigation shows limited effect of primary
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health care diagnoses on CHA2DS2-VASc score (57). There are also limitations in matching of treatment cohorts. Even though matching was used to control for confounders, there is potential
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for other important confounding factors not being included as variables. There could be reasons for choosing a specific DOAC that cannot be adjusted for using ICD-10 codes. Appropriate use of
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reduced DOAC dose have not been verified and is based on individual physician decisions. Differences in proportion of inappropriately reduced dose between the DOACs could affect their clinical performance in comparison. Patients with previous experience of anticoagulation may have lower bleeding risk than average. However, the proportion of patients with prior treatment is small and this factor does not affect the direct comparisons between different DOACs. Lastly, edoxaban was not included in this study since the number of patients using edoxaban was low and the average treatment duration was short at the moment of registry data retrieval.
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Conclusion In this large real-world NVAF cohort of 25,843 patients, pairwise comparisons showed a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. Patients treated with reduced dose dabigatran had lower all-cause mortality than patients treated with apixaban or rivaroxaban. There were no differences in effectiveness. Despite full optimal matching there can still be a confounding by indication that cannot be corrected for using ICD-10 codes. Further studies of direct comparisons between DOACs,
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preferably a prospective comparative trial, are needed.
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Conflicts of interest Conflicts of interests: Bo Norrving has received honoraria for Data Monitoring Safety Board work for Astra Zeneca (SOCRATES AND THALES trials) and Bayer (NAVIGATE-ESUS trial). Anders Själander was the principal investigator of the RE-VERSE AD study in Sweden and has received consultancy and lecture fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, Takeda Pharma and Pfizer.
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authors have declared that no competing interests exist.
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Sara Själander has received lecture fees from Boehringer-Ingelheim and Pfizer. The other
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Sources of funding This work was supported by The Swedish Heart-Lung Foundation, grant number
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20150435, https://www3.hjart-lungfonden.se/ViewPublicReport.aspx (AS)
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Tables and figures
Journal Pre-proof Table 1. Baseline clinical characteristics of treatment groups prior to weighting, presented as n (%) Apixaban (n=11493) 205 (83-381)
352 (111-750) 267 (102-532) 74 (68-81) 4436 (56.2)
1242 (10.8) 1505 (13.1) 1472 (12.8) 1558 (13.6) 238 (2.1) 1919 (16.7) 300 (2.6) 2049 (17.8) 7243 (63,0) 635 (5.5) 1827 (15.9) 2395 (20.8) 850 (7.4) 2383 (20.7) 159 (1.4) 1953 (17,0) 4150 (36.1) 3406 (29.6)
462 (7.2) 742 (11.5) 692 (10.7) 574 (8.9) 60 (0.93) 924 (14.3) 237 (3.7) 924 (14.3) 3670 (56.9) 158 (2.4) 796 (12.3) 1106 (17.1) 436 (6.8) 997 (15.5) 100 (1.5) 820 (12.7) 2453 (38,0) 1974 (30.6)
794 (10.1) 1051 (13.3) 976 (12.4) 1048 (13.3) 187 (2.4) 1362 (17.2) 265 (3.4) 1429 (18.1) 5030 (63.7) 309 (3.9) 1112 (14.1) 1510 (19.1) 591 (7.5) 1562 (19.8) 118 (1.5) 1288 (16.3) 3234 (41,0) 1898 (24,0)
316 (2.7) 240 (2.1) 114 (0.99) 38 (0.33) 833 (7.2) 3087 (26.9) 2354 (20.5)
158 (2.4) 123 (1.9) 57 (0.88) 22 (0.34) 295 (4.6) 1397 (21.6) 1102 (17.1)
207 (2.6) 148 (1.9) 82 (1,0) 23 (0,29) 514 (6.5) 2060 (26.1) 1615 (20.5)
1026 (8.9) 148 (1.3)
433 (6.7) 67 (1,0)
663 (8.4) 113 (1.4)
10451 (90.9) 1015 (8.8) 27 (0.23)
5941 (92.1) 497 (7.7) 15 (0.23)
7297 (92.4) 576 (7.3) 24 (0.3)
3 (2-4) 511 (4.4) 1626 (14.1) 2401 (20.9) 2427 (21.1) 1881 (16.4) 1397 (12.2) 803 (7,0) 362 (3.1) 85 (0.7)
2 (1-4) 617 (9.6) 1313 (20.3) 1536 (23.8) 1210 (18.8) 826 (12.8) 535 (8.3) 285 (4.4) 105 (1.6) 26 (0.4)
3 (2-4) 329 (4.2) 1165 (14.8) 1694 (21.5) 1696 (21.5) 1265 (16) 923 (11.7) 515 (6.5) 260 (3.3) 50 (0.6)
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aCHA
Rivaroxaban (n=7897)
75 (68-82) 6361 (55.3)
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Duration of follow-up Median, days (IQR) Demographic characteristics Age (years), mean (IQR) Male gender Prior medical conditions Anemia Cancer Chronic Obstructive Pulmonary Disease Congestive Heart Failure Dementia Diabetes Excessive alcohol use Fall Hypertension Renal failure Ischemic stroke Stroke or TIA TIA Vascular disease Liver disease Myocardial infarction Prior warfarin Reduced dose regime Prior bleeding Intracranial bleeding Intracerebral bleeding Traumatic intracranial bleeding Both intracerebral and traumatic bleeding Gastrointestinal bleeding Major bleeding Other bleeding Prior cardiovascular intervention Percutaneous coronary intervention (PCI) PCI with stenting Indication for treatment Primary stroke prevention in AF Secondary prevention after stroke in AF Secondary prevention after peripheral arterial emboli in AF CHA2DS2-VASc scorea Median 0 1 2 3 4 5 6 7 8
Dabigatran (n=6453)
2DS2-VASc score = 1 point each (except where noted) for history of congestive heart failure, hypertension, aged ≥75 years (2 points), diabetes mellitus, previous stroke or TIA or thromboembolism (2 points), vascular disease, female sex and aged 65-74 years.
Journal Pre-proof Table 2. Baseline clinical characteristics in weighted cohorts, presented as %. Dabigatran (n=6453)
Rivaroxaban (n=7897)
73,5 (10,3) 57.0
72,3 (9,8) 58.0
73,5 (10,3) 57.0
13.0 17.0 3.1 62.0 1.5 16 21.0 4.5 20.0 38 28.0
11.0 16.0 3.2 62.0 1.4 15.0 20.0 3.9 19.0 38 28.0
12.0 16.0 3.1 6.2 1.5 16.0 21.0 4.3 19.0 38.0 28.0
6.5 2.6 20
6.1 2.6 19.0
6.4 2.7 20.0
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8.0
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Demographic characteristics Age (years), mean (SD) Male gender Prior medical conditions Congestive Heart Failure Diabetes Excessive alcohol use Hypertension Liver disease Myocardial infarction Vascular disease Renal failure Stroke/TIA Prior warfarin Reduced dose regime Prior bleeding Gastrointestinal bleeding Intracranial bleeding Other bleeding Prior cardiac intervention PCIa
Apixaban (n=11493)
Apixaban Events 80 20 40 224 120 125 496 125 105 83 115
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Time 8061.0 8080.6 8077.8 8004.4 8030.5 8033.0 8084.6 8033.0 8038.7 8044.4 8033.7
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Outcome Gastrointestinal bleeding Hemorrhagic stroke Intracranial bleeding Major bleeding Other bleeding Myocardial infarction All-cause mortality Myocardial infarction All-cause stroke Ischemic stroke All-cause stroke and systemic embolism
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Table 3. Primary outcomes in treatment groups, time presented as years and rate as event per 100 years.
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Percutaneous coronary intervention
Rate 0.99 0.25 0.50 2.80 1.50 1.60 6.10 1.60 1.30 1.00 1.40
Time 8200.6 8243.5 8233.1 8137.5 8178.2 8193.5 8244.7 8193.5 8187.4 8188.6 8186.5
Dabigatran Events 84 6 26 186 101 79 246 79 84 78 91
Rate 1.00 0.07 0.32 2.30 1.20 0.93 3.00 0.93 1.00 0.95 1.10
Time 7496.4 7546.0 7535.0 7405.5 7456.0 7513.4 7550.1 7513.4 7494.7 7499.7 7490.1
Rivaroxaban Events 119 30 52 308 176 96 438 96 113 818 120
Rate 1.60 0.40 0.69 4.20 2.40 1.30 5.80 1.30 1.50 1.10 1.60
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Figure 1. Flow chart of cohort formation
Flow chart of the cohort formation. Patients with DOAC in the registry were 34 624, Then, 2 342 patients were excluded due to nonstandard dosage (i.e. prophylaxis in orthopedic surgery). Following, 4 424 patients without atrial fibrillation indication, 130 patients with valvular atrial fibrillation and 1 885 patients with previous DOAC treatment were excluded, forming a study cohort of 25 843 patients.
Journal Pre-proof Figure 2. Hazard ratios in direct comparisons after weighting
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Hazard ratios in direct comparisons of primary outcomes with different novel oral anticoagulants, presented for both standard as reduced dose regimen.
Journal Pre-proof Figure 3. Cumulative incidence (%) of outcomes after weighting.
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Kaplan-Meier curves presenting cumulative incidence of primary outcomes in apixaban (green), dabigatran (orange) and rivaroxaban (blue).
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Appendix A. Supplementary data
Journal Pre-proof Table 1. ICD-10-codes used in medical history Criteria
History of fall
≥2 occurrences of W00–W19
Cancer
C00–C26, C30–C41, C43–C58, C60–C97
Stroke
I60, I61, I63, I64, I69
Transient ischaemic attack (TIA)
G45 (except G454)
Stroke or TIA
I63, I64, I69, G45 (except G454)
Hypertension
I10–I13, I15
Congestive heart failure
I110, I130, I132, I50
Diabetes
E10–14
Myocardial infarction
I21, I252
Ischaemic heart disease
I20–I23, I241, I248, I249, I251, I252, I255, I256, I258, I259
Chronic obstructive pulmonary disease Anaemia
J43, J44
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Item in medical history
Cerebral haemorrhage
I60, I61
Previous traumatic intracranial bleeding Renal failure
S064–S066
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Intracranial bleeding
D50, D510, D513, D518, D519, D52, D53, D55, D560–562, D568, D569, D570–D572, D588, D589, D59–D64 D629, I60–I62, I850, I983, K250, K252, K254, K256, K260, K262, K264, K266, K270, K272, K274, K276, K280, K282, K284, K286, K625, K920, K922 I850, I983, K250, K252, K254, K256, K260, K262, K264, K266, K270, K272, K274, K276, K280, K282, K284, K286, K625, K920, K922 I60–I62, S064–S066
Dementia Liver disease Vascular disease PCI
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Excessive alcohol use
I120, I131, I132, N182–N185, N189, DR016, DR024, KAS00, KAS10, KAS20 E244, F10, G312, G621, G721, I426, K292, K70, T51, Y90, Y91, K860, O354, Z714 F00–F03
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Gastrointestinal bleeding
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Major bleeding
K70–K77, JJB, JJC I21, I22, I252, I70–I73 Z955
Journal Pre-proof Table 2. ICD-10-codes used in identifying outcomes
Ischaemic stroke Haemorrhagic stroke Major bleeding Intracranial bleeding Gastrointestinal bleeding Other bleeding
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All-cause mortality Myocardial infarction
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All-cause stroke
Criteria NPRa: I60, RSb: I61, I63, I64, NPR: I74 NPR: I60, RS: I61, I63, I64 RS: I63 NPR: I60, RS: I61 Any of intracranial, gastrointestinal, or other bleeding NPR: I60, RS: I61, NPR: I62, S064–066 I850, I983, K250, K252, K254, K256, K260, K262, K264, K266, K270, K272, K274, K276, K280, K282, K284, K286, K625, K920–922 H113, H313, H356, H431, H450, H922, I312, J942, M250, N02, N501A, N938, N939, N950, R04, R319, R58, T810, D500, D508, D509, D629 Presence in the Swedish cause of death register I21, I22
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Outcome All-cause stroke and systemic embolism
aNational
Patient Registry, b Swedish Stroke Register
Journal Pre-proof Table 3.”At-risk”
aAll-cause
Time 1 1657,1 565,5 2887,5 1293,1 2437,7 888,6 1647,1 557 2877,9 1278,1 2425,6 877,7 1656,5 564,5 2887,5 1293,1 2436,8 887 1646,6 555 2877,9 1278,1 2424,7 876,1 1646,2 552,7 2877,9 1278,1 2422,7 873,9 1656,5 564 2885,9 1293,1 2432,1 885,3 1652,6 561,8 2880,2 1269,9 2419,6 879 1638,9 554,8 2870,6 1273,6 2412,4 864 1634,7 552 2861,6 1260,8 2395,9 853,5
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Time 0.5 3316,7 1294,9 3812,1 1686,2 3832 1508,7 3299,1 1287,3 3802,3 1672,3 3821,7 1497,1 3316,7 1292,9 3810,1 1686,2 3830,2 1508,7 3299,1 1284,9 3800,3 1672,3 3819,9 1494,8 3298,7 1283,5 3800,3 1672,3 3817,9 1492,6 3316,7 1291,1 3808,4 1686,2 3828,5 1506,7 3307,6 1291,6 3802,8 1667,5 3811,6 1497 3304,5 1287,6 3796,1 1662,7 3808,3 1487,8 3295,3 1281,9 3785,1 1653,9 3788,4 1477,1
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Time 0 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421
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Count at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk
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Group highj lowk high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low
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Strata Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban
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Outcome ACMa ACM ACM ACM ACM ACM Istrokeb IStroke IStroke IStroke IStroke IStroke HemStrokec HemStroke HemStroke HemStroke HemStroke HemStroke ACStroked ACStroke ACStroke ACStroke ACStroke ACStroke ACSSEe ACSSE ACSSE ACSSE ACSSE ACSSE ICBleedf ICBleed ICBleed ICBleed ICBleed ICBleed GIBleedg GIBleed GIBleed GIBleed GIBleed GIBleed OthBleedh OthBleed OthBleed OthBleed OthBleed OthBleed MajBli MajBl MajBl MajBl MajBl MajBl
Time 1.5 773,5 232,2 2098 954,1 1544,6 550,1 771 227,3 2086,7 944,9 1531,4 541,5 772,1 231,2 2098 954,1 1542,8 548,5 769,6 226,8 2086,7 944,9 1529,5 539,8 769,2 225,9 2086,7 944,9 1529,5 539 772,1 231,2 2095 949,9 1540 543 770,6 231,8 2090,8 927,9 1526,6 539,1 763,1 229,5 2078,9 935 1522,7 530,3 760,7 228,1 2069,7 914,1 1507,6 516,1
Time 2 254,1 71,5 1506,7 672,9 922,3 271,3 252,3 71,5 1494,7 662 908,8 267,5 254,1 71,5 1506,7 672,9 921,4 271,3 252,3 71,5 1494,7 662 908 267,5 252,3 71,5 1494,7 662 908 266,7 254,1 71,5 1504 662,3 918,7 271,3 252,5 71 1497,5 650,8 909,2 268,8 247,5 70,5 1493,2 645,8 906,2 253,6 246,9 70 1483,4 625,8 893,3 252,5
mortality, bIschemic stroke, cHemorrhagic stroke, dAll-cause stroke, eAll-cause stroke and systemic embolism, fIntracranial bleeding, gGastrointestinal bleeding, hOther bleeding, iMajor bleeding, jstandard dose, kreduced dose.
Time 2.5 17,9 11,4 974,9 445,5 470,6 131,5 17,9 11,4 966,2 435,8 460,9 128,9 17,9 11,4 974,9 445,5 470,6 131,5 17,9 11,4 966,2 435,8 460,9 128,9 17,9 11,4 966,2 435,8 460,9 128,9 17,9 11,4 973,2 442,2 467,9 131,5 17,9 11,4 969,9 428,4 464,5 129 17,9 11,4 963 426,6 460,3 118,4 17,9 11,4 957,8 414,1 452,2 117,2
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M. Jansson, S. Själander, V. Sjögren, H. Renlund, B. Norrving, A. Själander PII:
S0049-3848(19)30496-7
DOI:
https://doi.org/10.1016/j.thromres.2019.11.010
Reference:
TR 7514
To appear in:
Thrombosis Research
Received date:
6 April 2019
Revised date:
1 November 2019
Accepted date:
11 November 2019
Please cite this article as: M. Jansson, S. Själander, V. Sjögren, et al., Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and rivaroxaban in atrial fibrillation, Thrombosis Research (2019), https://doi.org/10.1016/ j.thromres.2019.11.010
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© 2019 Published by Elsevier.
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Direct Comparisons of Effectiveness and Safety of Treatment with Apixaban, Dabigatran and Rivaroxaban in Atrial Fibrillation Jansson M, MD 1*; Själander S, MD, PhD1; Sjögren V, MD, PhD1; Renlund H, PhD2; Norrving B, MD, PhD3, Själander A, MD, PhD1
1Department
of Public Health and Clinical Medicine, Umeå University, Sundsvall, Sweden; Clinical Research Center, Uppsala University, Uppsala, Sweden 3Department of Clinical Sciences Lund, Neurology, Skåne University Hospital, Lund University, Lund, Sweden
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*Correspondence:
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2Uppsala
Martin Jansson, MD Cardiology department Sundsvall Hospital 856 43 Sundsvall Sweden
Phone: +46768144039 Email: [email protected]
Manuscript word count: 2931
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Highlights Direct oral anticoagulant (DOAC) treatment prevents embolism in atrial fibrillation patients
Effectiveness and safety discrepancies among different DOACs are not well understood
Standard dose apixaban and dabigatran carries lower bleeding risk than rivaroxaban
Reduced dose apixaban carries lower bleeding risk than rivaroxaban and dabigatran
No statistically significant differences in effectiveness were found
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Abstract Introduction: Direct oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran. Materials and methods: Patients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015.
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Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC
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and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched
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using full optimal matching and directly compared.
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Results: A total of 25,843 NVAF patients were included. Patients treated with standard dose
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apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54-0.88) and HR 0.64 (95% CI 0.48-0.87). Regarding reduced dose, patients
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treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44-0.88) and HR 0.45 (95% CI 0.33-0.61). In reduced dose,
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patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found.
Conclusions: In this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.
Keywords Dabigatran, Rivaroxaban, Treatment Outcome, Apixaban, Anticoagulants, Atrial Fibrillation
Abbreviations DOACs (direct oral anticoagulants), NVAF (non-valvular atrial fibrillation), AF (atrial fibrillation), VKAs (vitamin K antagonists), OAC (oral anticoagulant), NPR (National Patient
Journal Pre-proof Registry), PPV (positive predictive value), ATC (Anatomic Therapeutic Chemical) SAH (subarachnoid hemorrhage), ICH (intracerebral hemorrhage)
Background Atrial fibrillation (AF) is the most common cardiac arrhythmia (1). A retrospective registry study with data from the Swedish Patient Register determined the Swedish adult prevalence of AF to be 2.9%, undiagnosed atrial fibrillation excluded, as well as atrial fibrillation treated in primary care only (2). Additionally, the overall prevalence of AF is increasing continuously, partly due to enhanced surveillance (3). AF is an independent risk factor for stroke, increasing
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stroke risk by near fivefold (1, 4). Furthermore, AF in patients with ischemic stroke is associated
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with higher mortality (5).
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Vitamin K antagonists (VKAs), e.g. warfarin, have been the standard of care for anticoagulation in patients with AF for the last 50 years (6). Anticoagulation with warfarin in
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patients with non-valvular atrial fibrillation (NVAF) reduces the stroke risk by two-thirds (7).
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Oral anticoagulant (OAC) therapy is superior to placebo and aspirin in reduction of stroke risk (8, 9). Even though OAC therapy using warfarin increases the risk of hemorrhagic stroke (10),
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reduction of ischemic stroke risk outweighs the risk of bleeding on OAC therapy (11). This is
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true even for patients who are frail, elderly, and have frequent falls (12, 13). Currently, stroke risk stratification in patients with AF is done using the CHA2DS2-VASc risk score (congestive heart failure (1p), hypertension (1p), age ≥75 years (2p), diabetes mellitus (1p), previous stroke/TIA (2p), vascular disease (1p), age 65-74 years (1p), sex category (female equals 1p)) (14). The European Society of Cardiology (ESC) recommends OAC in men with CHA2DS2-VASc ≥2p and women with ≥3p. Furthermore, treatment might be considered in men ≥1p and women with ≥2p (15). American College of Cardiology/American Heart Association recommend treatment in patients with CHA2DS2-VASc ≥2p (16) Vitamin K antagonists have several limitations including genetic variations in metabolism, various drug and food interactions and inertia in action onset and offset (6, 17, 18). Also, active cancer, dementia, major depression, chronic liver disease, poverty, longer distance to care and
Journal Pre-proof frequent hospitalizations influence quality of treatment (19, 20). Underuse of OAC therapy is common (21). Concerns of patient compliance, issues in monitoring and the need for doseadjusting VKA therapy are common reasons for withholding therapy (22). The many limitations of warfarin resulted in development of direct oral anticoagulants (DOACs). DOACs, including dabigatran, rivaroxaban, apixaban and edoxaban, are superior or non-inferior to warfarin in stroke prevention as well as having similar or lower risk of bleeding, as concluded in pivotal studies and subsequent observational studies (23-28).
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There are no direct comparisons of DOACs in randomized prospective trials. Previous
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comparisons of real-world data suggest that while rivaroxaban, dabigatran and apixaban have
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similar treatment effect regarding the risk of ischemic stroke, apixaban may be associated with a
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lower risk of major bleeding compared with the other two. (29-37). Our objective was to investigate whether effectiveness and safety differs among apixaban,
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rivaroxaban and dabigatran in direct pairwise comparisons in Sweden.
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Method The study was approved by the Ethics Review Board in Umeå (2015/142-31). The population of this study was identified from the Swedish anticoagulation quality registry Auricula. Auricula was launched in 2006 and contains information regarding OAC therapy in about 135 000 patients treated with either warfarin or DOAC. Information includes start and stop dates for treatment, indication for OAC treatment, INR values of patients on warfarin, prescribed dosage and creatinine levels in patients on DOAC. The register is continuously growing and includes both outpatient- and inpatient diagnoses of AF. It is used in a majority of
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Sweden´s healthcare regions, and where it is used, all anticoagulation treatments are registered
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in Auricula, with data on almost half of the Swedish patients with ongoing DOAC treatment at the
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time of data extraction. NVAF patients who were registered in Auricula and started on a new treatment period with dabigatran, rivaroxaban or apixaban between January 1, 2013, and
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December 31, 2015 were included. Patients with ongoing OAC treatment at January 1, 2013,
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were excluded. However, a previous period with OAC therapy was allowed. Patients with
indication valvular atrial fibrillation were excluded (Fig 1). New treatment was defined as a
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patient that was instituted on a DOAC for the first time. A switch from one DOAC to another was
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not allowed, but a patient could previously have been on Vitamin K antagonist. The study used an “as-treated” exposure definition considering the whole treatment period, short drug discontinuations were allowed.
Previous medical illnesses and most events during follow up (endpoints) were retrieved from the National Patient Registry (NPR), a Swedish health care administrative registry founded in 1964 and managed by the Swedish National Board of Health and Welfare. Co-morbidities and past medical event history were identified using ICD-10 (International Classification of Diseases 10th edition) codes. The NPR contains information from specialized inpatient and outpatient care. The degree of coverage is close to 100 % regarding inpatient care. Only 0.8 % of discharged patients are missing an ICD-10 code as main diagnosis, and external validation of the NPR has concluded a positive predictive value (PPV) of a diagnosis as high as 85-95% (38). PPV of the
Journal Pre-proof diagnosis atrial fibrillation is 97% (39). ICD-10-codes used in medical history are listed in Table 1, Appendix. Date of death of deceased persons was collected from the Swedish Cause of Death registry. The Swedish Stroke Register (Riksstroke), the national quality registry of stroke care in Sweden, was used for identification of events of intracerebral hemorrhage and ischemic stroke during the study period. This is motivated by higher validity for stroke diagnoses than the NPR. Also, it is possible for the same index stroke to be registered twice in the NPR. Coverage of
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Riksstroke was estimated to be 89 % in 2017 and has been stable during the time period of the
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study (40).
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Information concerning concurrent medication was retrieved from the Swedish Dispensed
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Drugs Registry using ATC (Anatomic Therapeutic Chemical) codes. The registry is managed by
compulsory for all pharmacies.
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the National Board of Health and Welfare and has complete coverage since reporting is
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Outcome events (endpoints) were ischemic stroke, all-cause stroke and systemic embolism, myocardial infarction, all-cause mortality, hemorrhagic stroke, or major bleeding that
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was fatal or required hospital care. Blood transfusion was not counted as a major bleeding event, due to lack of information on number of transfusions in the ICD10 codes. Death was identified in the Cause of Death registry while ischemic stroke and intracerebral hemorrhage were identified in Riksstroke. Remaining outcome events were extracted from the NPR. Hemorrhagic stroke was defined as either subarachnoid hemorrhage (SAH), retrieved from the NPR, or intracerebral hemorrhage (ICH). ICH was by itself an endpoint while also being included in all-cause stroke, intracranial bleeding, hemorrhagic stroke, and major bleeding. Every patient could be registered with up to three types of bleeding; gastrointestinal, intracranial (including ICH, SAH, subdural and epidural bleeding) and/or other bleeding. Only the first occurrence of each type of endpoint was included in the analyses.
Journal Pre-proof In short, all outcomes that were fatal or required specialist care, as well as stroke of any severity, were registered and analyzed. ICD-10-codes used in identification of outcomes are listed in Table 2, Appendix. 2.1 Statistical methods Full optimal matching was used in statistical analysis. An optimal matching between two groups creates clusters of individuals from both groups such that some metric is minimized globally. A full matching does not discard any individuals. Using the R package optmatch we created full
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optimal matchings between apixaban and rivaroxaban, rivaroxaban and dabigatran and
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dabigatran and apixaban, all based on the Mahalanobis distance between a set of matching covariates (Table 2) (41). We combined these to get the study population partitioned into
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clusters containing individuals from all three groups, with a weighting such that each cluster
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was balanced, and the total weight equaled the study population size. In this way the weighted
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groups look more similar in baseline covariates, and any parametric analysis is less vulnerable to model misspecification (42). Outcomes were analyzed via adjusted and weighted Cox
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regression, with standard errors from robust (sandwich) estimators.
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Results 3.1 Cohort description In total, the study included 25,843 NVAF patients. Of these, 11,493 were treated with apixaban, 6,453 with dabigatran and 7,897 with rivaroxaban. Baseline patient characteristics of the unmatched study sample are presented in Table 1. The mean patient age in the apixaban group was 75 years, in the dabigatran group 70 years and in the rivaroxaban group 74 years. In the apixaban group, 55.3% were male, with corresponding figures of 61.5% and 56.2% in the dabigatran and rivaroxaban groups, respectively. The median CHA2DS2VASc score was 2 for
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dabigatran, and 3 for the apixaban and rivaroxaban groups. After matching, there were no
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significant differences in baseline patient characteristics between apixaban vs dabigatran,
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apixaban vs rivaroxaban and dabigatran vs. rivaroxaban. Baseline patient characteristics of the matched cohorts are presented in Table 2. The mean patient age in the matched apixaban and
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rivaroxaban groups was 73.5 years, while in the matched dabigatran group 72.3 years. The
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matched apixaban and rivaroxaban groups had 57% male gender, compared to 58% in the
3.2 Primary outcomes
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matched dabigatran group.
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After matching, there were no significant differences in rates of all cause stroke and systemic embolism between the three DOACs. There were also no significant differences in ischemic stroke rates (Fig 2, Fig 3). Event rates of primary outcomes are presented in Table 3. Apixaban vs dabigatran There were no statistically significant differences in primary outcomes when comparing apixaban and dabigatran in standard dose. In reduced dose, apixaban treatment carried lower risk of major bleeding and gastrointestinal bleeding, HR 0.62 (95% CI 0.44-0.88) and HR 0.42 (95% CI 0.24-0.70). However, dabigatran treatment carried lower risk of all-cause mortality, HR 1,14 (95% CI 1.10-1.80) (Fig 2). Apixaban vs rivaroxaban
Journal Pre-proof In standard dose, apixaban treatment carried lower risk of major bleeding and gastrointestinal bleeding, HR 0.69 (95% CI 0.54-0.88) and HR 0.57 (95% CI 0.38-0.86). Also, apixaban treatment carried a lower risk of other bleeding, HR 0.70 (95% CI 0.51-0.96). In reduced dose, apixaban treatment carried a lower risk of hemorrhagic stroke and major bleeding, HR 0.36 (95% CI 0.130.99) and HR 0.45 (95% CI 0.33-0.61). Further considering reduced dose, apixaban treatment carried a lower risk of intracranial bleeding, gastrointestinal bleeding and other bleeding with HR 0.41 (95% CI 0.21-0.80), HR 0.51 (95% CI 0.32-0.80) and HR 0.42 (95% CI 0.25-0.63)
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respectively.
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Dabigatran vs rivaroxaban
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In standard dose, dabigatran treatment carried lower risk of major bleeding and other bleeding, HR 0.64 (95% CI 0.46-0.87) and HR 0.61 (95% CI 0.40-0.92). In reduced dose, dabigatran
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0.86) and HR 0.68 (95% CI 0.52-0.89).
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treatment carried a lower risk of other bleeding and all-cause mortality, HR 0.56 (95% CI 0.36-
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Discussion This study was designed to investigate differences in effectiveness and safety associated with different DOACs through matched and adjusted analyses in a setting of high-quality anticoagulation (27). In this cohort study, real-world data show a lower risk of major bleeding among NVAF patients treated with standard dose apixaban or dabigatran than those treated with rivaroxaban. When comparing type of bleeding, patients treated with apixaban have lower risk of gastrointestinal and other bleeding compared to patients treated with rivaroxaban.
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Patients treated with standard dose dabigatran have lower risk of other bleeding compared to patients treated with rivaroxaban. The study could not show any statistically significant
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difference in risk of major bleeding when comparing apixaban and dabigatran. Data in this study
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also show a lower risk of major bleeding among NVAF patients treated with reduced dose
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apixaban than for those treated with reduced dose dabigatran or rivaroxaban. When comparing type of bleeding, patients treated with reduced dose apixaban have lower risk of hemorrhagic
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stroke, intracranial bleeding, gastrointestinal bleeding and other bleedings than patients treated with reduced dose rivaroxaban, while only the risk of gastrointestinal bleeding is lower
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compared to patients treated with reduced dose dabigatran. Furthermore, patients treated with
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reduced dose dabigatran have lower risk of other bleeding compared to patients treated with reduced dose rivaroxaban. Also, patients treated with reduced dose dabigatran have lower allcause mortality than patients treated with reduced dose apixaban or rivaroxaban. We found no statistically significant differences in effectiveness considering all-cause stroke and systemic embolism. Previous findings through clinical trials and meta-analyses conclude DOACs as superior or non-inferior to warfarin in prevention of stroke and systemic embolism as well as having similar or lower risk of bleeding (23-25, 43-48). Recent observational studies comparing DOACs vs. warfarin have reproduced these findings (27-29, 49-51). In addition, observational studies and meta-analyses comparing DOACs vs. warfarin indicate a lower risk of major bleeding with use of dabigatran and apixaban compared with use of rivaroxaban (47, 51-54). Also,
Journal Pre-proof previous studies comparing effectiveness and safety of individual DOAC without using warfarin as indirect comparator (31, 36, 37, 55, 56). One US study compared rivaroxaban and dabigatran treatment among elderly with NVAF. The study was restricted to anticoagulant naive patients and only standard-dose regimes were compared. Dabigatran was associated with decreased risk of major bleeding compared to rivaroxaban (55). In addition, two other US administrative claims database studies have investigated safety and effectiveness among NVAF patients on dabigatran, rivaroxaban or apixaban and show decreased risk of major bleeding associated with both
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dabigatran and apixaban compared to rivaroxaban (31, 56). However, patients with previous
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use of other anticoagulants were included and no distinction was made between dosing regimens (31, 56). Also, a recent Danish study showed no statistical significance in either risk of
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stroke and systemic embolism or risk of major bleeding when directly comparing rivaroxaban,
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dabigatran and apixaban in propensity score matched cohorts, thus, not replicating previous findings. However, matching used the nearest neighbor algorithm, and only patients with
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standard dosing were studied, which could partly explain why their results differs from ours
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(36). Also, a previous meta-analysis of real-world data suggest that while rivaroxaban, dabigatran and apixaban have similar treatment effect regarding the risk of ischemic stroke,
(37).
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apixaban may be associated with a lower risk of major bleeding compared with the other two.
The results of our study confirm previous findings, showing no statistically significant difference in prevention of stroke or systemic embolism and a favorable bleeding risk profile for apixaban and dabigatran vs. rivaroxaban. This could either be due to actual differences in bleeding risk between these DOACs, or a propensity for the clinicians to choose rivaroxaban due to the once daily dosing regime in patients with perceived worse compliance. Likewise, the lower all-cause mortality seen in patients on low-dose dabigatran might be due to confounding by indication that remains despite the matching procedure. To our knowledge, our study is the first to directly compare (without warfarin as indirect comparator) both standard and reduced dose regimes of apixaban, dabigatran and rivaroxaban among anticoagulant naive
Journal Pre-proof patients in a full optimal matching design, showing statistically significant differences in safety among individual DOAC. With current recommendations of DOACs as first-line anticoagulant therapy for NVAF patients, this study contributes new findings from a clinical practice setting concerning individual risks and benefits associated with different DOACs in direct comparison (14). 4.1 Limitations The main limitation of this study is the non-randomized, retrospective design, not allowing for
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causal relationship between treatment and outcome being established. Also, although patients
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picked up their prescribed medication from a pharmacy, this does not mean that the medication was taken as prescribed. Diagnosis codes may be incorrectly coded, and may not be indicative of
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disease. Furthermore, some diagnoses are probably missing since there is no data on diagnoses
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from primary health care. However, a previous investigation shows limited effect of primary
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health care diagnoses on CHA2DS2-VASc score (57). There are also limitations in matching of treatment cohorts. Even though matching was used to control for confounders, there is potential
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for other important confounding factors not being included as variables. There could be reasons for choosing a specific DOAC that cannot be adjusted for using ICD-10 codes. Appropriate use of
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reduced DOAC dose have not been verified and is based on individual physician decisions. Differences in proportion of inappropriately reduced dose between the DOACs could affect their clinical performance in comparison. Patients with previous experience of anticoagulation may have lower bleeding risk than average. However, the proportion of patients with prior treatment is small and this factor does not affect the direct comparisons between different DOACs. Lastly, edoxaban was not included in this study since the number of patients using edoxaban was low and the average treatment duration was short at the moment of registry data retrieval.
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Conclusion In this large real-world NVAF cohort of 25,843 patients, pairwise comparisons showed a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. Patients treated with reduced dose dabigatran had lower all-cause mortality than patients treated with apixaban or rivaroxaban. There were no differences in effectiveness. Despite full optimal matching there can still be a confounding by indication that cannot be corrected for using ICD-10 codes. Further studies of direct comparisons between DOACs,
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preferably a prospective comparative trial, are needed.
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Conflicts of interest Conflicts of interests: Bo Norrving has received honoraria for Data Monitoring Safety Board work for Astra Zeneca (SOCRATES AND THALES trials) and Bayer (NAVIGATE-ESUS trial). Anders Själander was the principal investigator of the RE-VERSE AD study in Sweden and has received consultancy and lecture fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, Takeda Pharma and Pfizer.
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authors have declared that no competing interests exist.
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Sara Själander has received lecture fees from Boehringer-Ingelheim and Pfizer. The other
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Sources of funding This work was supported by The Swedish Heart-Lung Foundation, grant number
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20150435, https://www3.hjart-lungfonden.se/ViewPublicReport.aspx (AS)
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Tables and figures
Journal Pre-proof Table 1. Baseline clinical characteristics of treatment groups prior to weighting, presented as n (%) Apixaban (n=11493) 205 (83-381)
352 (111-750) 267 (102-532) 74 (68-81) 4436 (56.2)
1242 (10.8) 1505 (13.1) 1472 (12.8) 1558 (13.6) 238 (2.1) 1919 (16.7) 300 (2.6) 2049 (17.8) 7243 (63,0) 635 (5.5) 1827 (15.9) 2395 (20.8) 850 (7.4) 2383 (20.7) 159 (1.4) 1953 (17,0) 4150 (36.1) 3406 (29.6)
462 (7.2) 742 (11.5) 692 (10.7) 574 (8.9) 60 (0.93) 924 (14.3) 237 (3.7) 924 (14.3) 3670 (56.9) 158 (2.4) 796 (12.3) 1106 (17.1) 436 (6.8) 997 (15.5) 100 (1.5) 820 (12.7) 2453 (38,0) 1974 (30.6)
794 (10.1) 1051 (13.3) 976 (12.4) 1048 (13.3) 187 (2.4) 1362 (17.2) 265 (3.4) 1429 (18.1) 5030 (63.7) 309 (3.9) 1112 (14.1) 1510 (19.1) 591 (7.5) 1562 (19.8) 118 (1.5) 1288 (16.3) 3234 (41,0) 1898 (24,0)
316 (2.7) 240 (2.1) 114 (0.99) 38 (0.33) 833 (7.2) 3087 (26.9) 2354 (20.5)
158 (2.4) 123 (1.9) 57 (0.88) 22 (0.34) 295 (4.6) 1397 (21.6) 1102 (17.1)
207 (2.6) 148 (1.9) 82 (1,0) 23 (0,29) 514 (6.5) 2060 (26.1) 1615 (20.5)
1026 (8.9) 148 (1.3)
433 (6.7) 67 (1,0)
663 (8.4) 113 (1.4)
10451 (90.9) 1015 (8.8) 27 (0.23)
5941 (92.1) 497 (7.7) 15 (0.23)
7297 (92.4) 576 (7.3) 24 (0.3)
3 (2-4) 511 (4.4) 1626 (14.1) 2401 (20.9) 2427 (21.1) 1881 (16.4) 1397 (12.2) 803 (7,0) 362 (3.1) 85 (0.7)
2 (1-4) 617 (9.6) 1313 (20.3) 1536 (23.8) 1210 (18.8) 826 (12.8) 535 (8.3) 285 (4.4) 105 (1.6) 26 (0.4)
3 (2-4) 329 (4.2) 1165 (14.8) 1694 (21.5) 1696 (21.5) 1265 (16) 923 (11.7) 515 (6.5) 260 (3.3) 50 (0.6)
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aCHA
Rivaroxaban (n=7897)
75 (68-82) 6361 (55.3)
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Duration of follow-up Median, days (IQR) Demographic characteristics Age (years), mean (IQR) Male gender Prior medical conditions Anemia Cancer Chronic Obstructive Pulmonary Disease Congestive Heart Failure Dementia Diabetes Excessive alcohol use Fall Hypertension Renal failure Ischemic stroke Stroke or TIA TIA Vascular disease Liver disease Myocardial infarction Prior warfarin Reduced dose regime Prior bleeding Intracranial bleeding Intracerebral bleeding Traumatic intracranial bleeding Both intracerebral and traumatic bleeding Gastrointestinal bleeding Major bleeding Other bleeding Prior cardiovascular intervention Percutaneous coronary intervention (PCI) PCI with stenting Indication for treatment Primary stroke prevention in AF Secondary prevention after stroke in AF Secondary prevention after peripheral arterial emboli in AF CHA2DS2-VASc scorea Median 0 1 2 3 4 5 6 7 8
Dabigatran (n=6453)
2DS2-VASc score = 1 point each (except where noted) for history of congestive heart failure, hypertension, aged ≥75 years (2 points), diabetes mellitus, previous stroke or TIA or thromboembolism (2 points), vascular disease, female sex and aged 65-74 years.
Journal Pre-proof Table 2. Baseline clinical characteristics in weighted cohorts, presented as %. Dabigatran (n=6453)
Rivaroxaban (n=7897)
73,5 (10,3) 57.0
72,3 (9,8) 58.0
73,5 (10,3) 57.0
13.0 17.0 3.1 62.0 1.5 16 21.0 4.5 20.0 38 28.0
11.0 16.0 3.2 62.0 1.4 15.0 20.0 3.9 19.0 38 28.0
12.0 16.0 3.1 6.2 1.5 16.0 21.0 4.3 19.0 38.0 28.0
6.5 2.6 20
6.1 2.6 19.0
6.4 2.7 20.0
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Demographic characteristics Age (years), mean (SD) Male gender Prior medical conditions Congestive Heart Failure Diabetes Excessive alcohol use Hypertension Liver disease Myocardial infarction Vascular disease Renal failure Stroke/TIA Prior warfarin Reduced dose regime Prior bleeding Gastrointestinal bleeding Intracranial bleeding Other bleeding Prior cardiac intervention PCIa
Apixaban (n=11493)
Apixaban Events 80 20 40 224 120 125 496 125 105 83 115
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Time 8061.0 8080.6 8077.8 8004.4 8030.5 8033.0 8084.6 8033.0 8038.7 8044.4 8033.7
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Outcome Gastrointestinal bleeding Hemorrhagic stroke Intracranial bleeding Major bleeding Other bleeding Myocardial infarction All-cause mortality Myocardial infarction All-cause stroke Ischemic stroke All-cause stroke and systemic embolism
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Table 3. Primary outcomes in treatment groups, time presented as years and rate as event per 100 years.
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Percutaneous coronary intervention
Rate 0.99 0.25 0.50 2.80 1.50 1.60 6.10 1.60 1.30 1.00 1.40
Time 8200.6 8243.5 8233.1 8137.5 8178.2 8193.5 8244.7 8193.5 8187.4 8188.6 8186.5
Dabigatran Events 84 6 26 186 101 79 246 79 84 78 91
Rate 1.00 0.07 0.32 2.30 1.20 0.93 3.00 0.93 1.00 0.95 1.10
Time 7496.4 7546.0 7535.0 7405.5 7456.0 7513.4 7550.1 7513.4 7494.7 7499.7 7490.1
Rivaroxaban Events 119 30 52 308 176 96 438 96 113 818 120
Rate 1.60 0.40 0.69 4.20 2.40 1.30 5.80 1.30 1.50 1.10 1.60
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Figure 1. Flow chart of cohort formation
Flow chart of the cohort formation. Patients with DOAC in the registry were 34 624, Then, 2 342 patients were excluded due to nonstandard dosage (i.e. prophylaxis in orthopedic surgery). Following, 4 424 patients without atrial fibrillation indication, 130 patients with valvular atrial fibrillation and 1 885 patients with previous DOAC treatment were excluded, forming a study cohort of 25 843 patients.
Journal Pre-proof Figure 2. Hazard ratios in direct comparisons after weighting
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Hazard ratios in direct comparisons of primary outcomes with different novel oral anticoagulants, presented for both standard as reduced dose regimen.
Journal Pre-proof Figure 3. Cumulative incidence (%) of outcomes after weighting.
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Kaplan-Meier curves presenting cumulative incidence of primary outcomes in apixaban (green), dabigatran (orange) and rivaroxaban (blue).
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Appendix A. Supplementary data
Journal Pre-proof Table 1. ICD-10-codes used in medical history Criteria
History of fall
≥2 occurrences of W00–W19
Cancer
C00–C26, C30–C41, C43–C58, C60–C97
Stroke
I60, I61, I63, I64, I69
Transient ischaemic attack (TIA)
G45 (except G454)
Stroke or TIA
I63, I64, I69, G45 (except G454)
Hypertension
I10–I13, I15
Congestive heart failure
I110, I130, I132, I50
Diabetes
E10–14
Myocardial infarction
I21, I252
Ischaemic heart disease
I20–I23, I241, I248, I249, I251, I252, I255, I256, I258, I259
Chronic obstructive pulmonary disease Anaemia
J43, J44
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Item in medical history
Cerebral haemorrhage
I60, I61
Previous traumatic intracranial bleeding Renal failure
S064–S066
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Intracranial bleeding
D50, D510, D513, D518, D519, D52, D53, D55, D560–562, D568, D569, D570–D572, D588, D589, D59–D64 D629, I60–I62, I850, I983, K250, K252, K254, K256, K260, K262, K264, K266, K270, K272, K274, K276, K280, K282, K284, K286, K625, K920, K922 I850, I983, K250, K252, K254, K256, K260, K262, K264, K266, K270, K272, K274, K276, K280, K282, K284, K286, K625, K920, K922 I60–I62, S064–S066
Dementia Liver disease Vascular disease PCI
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Excessive alcohol use
I120, I131, I132, N182–N185, N189, DR016, DR024, KAS00, KAS10, KAS20 E244, F10, G312, G621, G721, I426, K292, K70, T51, Y90, Y91, K860, O354, Z714 F00–F03
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Major bleeding
K70–K77, JJB, JJC I21, I22, I252, I70–I73 Z955
Journal Pre-proof Table 2. ICD-10-codes used in identifying outcomes
Ischaemic stroke Haemorrhagic stroke Major bleeding Intracranial bleeding Gastrointestinal bleeding Other bleeding
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All-cause mortality Myocardial infarction
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All-cause stroke
Criteria NPRa: I60, RSb: I61, I63, I64, NPR: I74 NPR: I60, RS: I61, I63, I64 RS: I63 NPR: I60, RS: I61 Any of intracranial, gastrointestinal, or other bleeding NPR: I60, RS: I61, NPR: I62, S064–066 I850, I983, K250, K252, K254, K256, K260, K262, K264, K266, K270, K272, K274, K276, K280, K282, K284, K286, K625, K920–922 H113, H313, H356, H431, H450, H922, I312, J942, M250, N02, N501A, N938, N939, N950, R04, R319, R58, T810, D500, D508, D509, D629 Presence in the Swedish cause of death register I21, I22
ro
Outcome All-cause stroke and systemic embolism
aNational
Patient Registry, b Swedish Stroke Register
Journal Pre-proof Table 3.”At-risk”
aAll-cause
Time 1 1657,1 565,5 2887,5 1293,1 2437,7 888,6 1647,1 557 2877,9 1278,1 2425,6 877,7 1656,5 564,5 2887,5 1293,1 2436,8 887 1646,6 555 2877,9 1278,1 2424,7 876,1 1646,2 552,7 2877,9 1278,1 2422,7 873,9 1656,5 564 2885,9 1293,1 2432,1 885,3 1652,6 561,8 2880,2 1269,9 2419,6 879 1638,9 554,8 2870,6 1273,6 2412,4 864 1634,7 552 2861,6 1260,8 2395,9 853,5
ro
of
Time 0.5 3316,7 1294,9 3812,1 1686,2 3832 1508,7 3299,1 1287,3 3802,3 1672,3 3821,7 1497,1 3316,7 1292,9 3810,1 1686,2 3830,2 1508,7 3299,1 1284,9 3800,3 1672,3 3819,9 1494,8 3298,7 1283,5 3800,3 1672,3 3817,9 1492,6 3316,7 1291,1 3808,4 1686,2 3828,5 1506,7 3307,6 1291,6 3802,8 1667,5 3811,6 1497 3304,5 1287,6 3796,1 1662,7 3808,3 1487,8 3295,3 1281,9 3785,1 1653,9 3788,4 1477,1
-p
Time 0 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421 6186 2421
re
Count at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk at.risk
lP
Group highj lowk high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low high low
na
Strata Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban Apixaban Apixaban Dabigatran Dabigatran Rivaroxaban Rivaroxaban
Jo ur
Outcome ACMa ACM ACM ACM ACM ACM Istrokeb IStroke IStroke IStroke IStroke IStroke HemStrokec HemStroke HemStroke HemStroke HemStroke HemStroke ACStroked ACStroke ACStroke ACStroke ACStroke ACStroke ACSSEe ACSSE ACSSE ACSSE ACSSE ACSSE ICBleedf ICBleed ICBleed ICBleed ICBleed ICBleed GIBleedg GIBleed GIBleed GIBleed GIBleed GIBleed OthBleedh OthBleed OthBleed OthBleed OthBleed OthBleed MajBli MajBl MajBl MajBl MajBl MajBl
Time 1.5 773,5 232,2 2098 954,1 1544,6 550,1 771 227,3 2086,7 944,9 1531,4 541,5 772,1 231,2 2098 954,1 1542,8 548,5 769,6 226,8 2086,7 944,9 1529,5 539,8 769,2 225,9 2086,7 944,9 1529,5 539 772,1 231,2 2095 949,9 1540 543 770,6 231,8 2090,8 927,9 1526,6 539,1 763,1 229,5 2078,9 935 1522,7 530,3 760,7 228,1 2069,7 914,1 1507,6 516,1
Time 2 254,1 71,5 1506,7 672,9 922,3 271,3 252,3 71,5 1494,7 662 908,8 267,5 254,1 71,5 1506,7 672,9 921,4 271,3 252,3 71,5 1494,7 662 908 267,5 252,3 71,5 1494,7 662 908 266,7 254,1 71,5 1504 662,3 918,7 271,3 252,5 71 1497,5 650,8 909,2 268,8 247,5 70,5 1493,2 645,8 906,2 253,6 246,9 70 1483,4 625,8 893,3 252,5
mortality, bIschemic stroke, cHemorrhagic stroke, dAll-cause stroke, eAll-cause stroke and systemic embolism, fIntracranial bleeding, gGastrointestinal bleeding, hOther bleeding, iMajor bleeding, jstandard dose, kreduced dose.
Time 2.5 17,9 11,4 974,9 445,5 470,6 131,5 17,9 11,4 966,2 435,8 460,9 128,9 17,9 11,4 974,9 445,5 470,6 131,5 17,9 11,4 966,2 435,8 460,9 128,9 17,9 11,4 966,2 435,8 460,9 128,9 17,9 11,4 973,2 442,2 467,9 131,5 17,9 11,4 969,9 428,4 464,5 129 17,9 11,4 963 426,6 460,3 118,4 17,9 11,4 957,8 414,1 452,2 117,2
Journal Pre-proof
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