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Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation
IJCA-26176; No of Pages 7 International Journal of Cardiology xxx (2017) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation☆ Niklas W. Andersson a,⁎, Henrik Svanström a, Marie Lund a, Björn Pasternak a,b, Mads Melbye a,c,d a
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark d Department of Medicine, Stanford University School of Medicine, Stanford, California, USA b c
a r t i c l e
i n f o
Article history: Received 11 September 2017 Received in revised form 15 February 2018 Accepted 9 March 2018 Available online xxxx Keywords: Non-valvular atrial fibrillation Direct oral anticoagulant Stroke Major bleeding Propensity-matched comparison
a b s t r a c t Background: The comparative effectiveness and safety of individual direct oral anticoagulants (DOACs) in clinical practice is largely unknown. The study objectives were to compare effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation (NVAF). Methods: Based on nationwide registers we established a population-based historical cohort study of 12,638 new users of standard dose DOACs (apixaban 5 mg twice daily, dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily) with NVAF in Denmark, July 2013 to March 2016. Patients were matched on propensity scores in a 1:1 ratio comparing apixaban vs. dabigatran (for a total of 6470 patients), apixaban vs. rivaroxaban (7352 patients), and rivaroxaban vs. dabigatran (5440 patients). Hazard ratios (HRs) for stroke or systemic embolism (effectiveness outcome) and major bleeding (safety outcome) were estimated. Results: In propensity-matched comparisons of the risk of stroke or systemic embolism, the HRs were 1.27 (95% confidence interval [CI], 0.82–1.96) for apixaban vs. dabigatran, 1.25 (95% CI, 0.87–1.79) for apixaban vs. rivaroxaban, and 1.17 (95% CI, 0.69–1.96) for rivaroxaban vs. dabigatran. For the risk of major bleeding, the HRs were 0.94 (95% CI, 0.62–1.41) for apixaban vs. dabigatran, 0.88 (95% CI, 0.64–1.22) for apixaban vs. rivaroxaban, and 1.35 (95% CI, 0.91–2.00) for rivaroxaban vs. dabigatran. Conclusions: Among patients with NVAF in routine clinical practice, there were no statistically significant differences in risk of stroke or systemic embolism or major bleeding in propensity-matched comparisons between apixaban, dabigatran, and rivaroxaban used in standard doses. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation is the most common arrhythmia in developed countries and is associated with an up to five-fold increased risk of stroke and with increased mortality [1–4]. Anticoagulants are critical for prevention of stroke, and since the introduction of direct oral anticoagulant (DOAC) drugs their use has become widespread in clinical practice [5–7].
Abbreviations: DOAC, direct oral anticoagulant; NVAF, non-valvular atrial fibrillation; ATC, Anatomic Therapeutic Classification system; ICD-10, International Classification of Diseases version 10; HR, hazard ratio; CI, confidence interval; TIA, transient ischemic attack; PPV, positive predictive value. ☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen, Denmark. E-mail address: [email protected] (N.W. Andersson).
Anticoagulant treatment for stroke prevention should be weighed against the primary concern of an increased risk of bleeding. In clinical trials, the efficacy of DOACs (apixaban, dabigatran, rivaroxaban, and edoxaban) has been shown to be at least non-inferior to warfarin, but with superior safety profiles, mainly due to lower rates of intracranial bleeding [8–17]. To date, however, no head-to-head trials comparing individual DOACs have been published. In network meta-analyses of randomized controlled trials (RCTs), similar rates of stroke and systemic embolism were found for apixaban, dabigatran, and rivaroxaban. Further, there were significantly lower risks of clinically relevant bleeding for apixaban compared to both dabigatran and rivaroxaban and for dabigatran compared to rivaroxaban [17–20]. However, potential heterogeneity in the included study populations and trial methodology might have influenced the validity of these indirect comparisons [8,17]. In the absence of RCTs comparing individual DOACs, observational studies utilizing data from clinical practice can provide means to assess the comparative effectiveness and safety of individual DOACs [20–22]. Given lack of randomization, observational studies are inherently
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Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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N.W. Andersson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
susceptible to confounding and other types of bias [23]. Careful attention and study designs that appropriately prioritize internal validity are therefore necessary. In a nationwide cohort study, we investigated the association between use of apixaban, dabigatran, and rivaroxaban and risk of stroke or systemic embolism and major bleeding among patients with non-valvular atrial fibrillation (NVAF).
2.4. Confounder control
2. Methods
2.5. Statistical analyses
2.1. Study design
Follow-up started on the index date and ended on the first instance of an outcome event, death, disappearance, emigration, one year after index date, end of treatment, switch to another DOAC or warfarin, or end of study period (March 31, 2016). All analyses were conducted using Cox proportional hazards regression, estimating hazard ratios (HRs) with 95% confidence intervals (CIs). The proportional hazard assumption was assessed using a Wald test for the interaction between time since index date and treatment. P values were based on Wald tests. All statistical tests were two-sided; CIs that did not overlap 1.0 were considered to indicate statistical significance. Analyses were performed with the use of SAS software 9.4. Subgroup analyses were conducted according to sex, age (≥65 years vs. b65 years), history of stroke or transient ischemic attack (TIA), and history of bleeding. In secondary analyses, we analyzed all-cause mortality along with subtypes of primary effectiveness and safety outcomes as well as fatal primary outcome events. The study was approved by the Danish Data Protection Agency. Ethics approval is not required for register-based research in Denmark.
We conducted a historical register-based cohort study from July 1, 2013 to March 31, 2016. The source population consisted of new users of apixaban, dabigatran, and rivaroxaban, aged 45 years of age or older, with a recent diagnosis of NVAF. The start of the study period was selected to avoid the inclusion of very early users of each of the included DOACs (dabigatran was introduced in Denmark August 2011; rivaroxaban February 2012; and apixaban, December 2012 [24]), who may have been selected individuals [25]. This study was designed with the purpose of maximizing internal validity allowing simpler interpretation and a more robust comparison of cohorts. Firstly, the study was restricted to new users of anticoagulants, with no previous use of any DOACs or warfarin within one year prior to study entry. The new user design reduced the potential influence from previous treatments with the study drugs or factors associated herewith which could otherwise bias the results [26]. Secondly, the study only included patients with a recent diagnosis of NVAF within 90 days prior to start of DOAC treatment to reduce confounding by indication as well as to ensure more similar time points in course of disease (details and International Classification of Diseases [ICD] codes for inclusion in Supplemental Table 1). Thirdly, the study was restricted to patients receiving standard dose treatment of DOAC (apixaban 5 mg twice daily, dabigatran 150 mg twice daily, and rivaroxaban 20 mg once daily) with the intention to reduce the potential for unmeasured confounding. Reduced dose of DOAC are generally prescribed to elderly patients and patients with more advanced comorbidity, such as renal disease, and is likely to be associated with poorer health and frailty; factors that are difficult to capture using register data. Fourth, to further reduce the potential for confounding by indication and unmeasured confounding, we excluded participants who: i) had major musculoskeletal surgery within the last 30 days, ii) had chronic kidney disease (stage 4, 5 or receiving dialysis), iii) had heart valve disorder, prosthesis, or surgical heart valve procedure, or iv) had venous thromboembolism within the last six months (see Supplemental Table 1 for further details). Fifth, propensity score matching was used to take into account a broad range of baseline characteristics that may potentially influence the risk of the outcome. The study included three sets of analyses in separate propensity score-matched cohorts. We estimated the risk of stroke or systemic embolism and major bleeding associated with use of apixaban compared with dabigatran in the first cohort, apixaban vs. rivaroxaban in the second cohort and rivaroxaban vs. dabigatran in the third cohort. The date of the first filled prescription for a DOAC was defined as the study index date. The primary effectiveness outcome was defined as a hospital admission with a primary or secondary diagnosis of stroke or systemic embolism. The primary safety outcome “major bleeding” was defined as a hospital admission with a diagnosis of intracranial bleeding, gastrointestinal bleeding (bleeding ulcer, hematemesis or melena) or other serious bleeding (anemia caused by bleeding, bleeding of unknown origin, bleeding of the respiratory or urinary tract, peritoneal, retinal or orbital bleeding). Outcome definitions are provided in Supplemental Table 2.
2.2. Data sources Individual-level data were linked between different registers using the unique personal identification number assigned to all inhabitants in Denmark. We established the cohort on the basis of records of diagnoses of NVAF obtained from the National Patient Register [27] and information on filled prescriptions of anticoagulants obtained from the Register of Medicinal Product Statistics [27,28]. Information on outcomes was obtained from the National Patient Register. Supplemental Table 1 list all study drugs with ATC (Anatomic Therapeutic Classification system)-codes. Data on potential confounders was obtained from the National Patient Register (medical history), the Danish Civil Registration System (demographic variables) [29] and the Register of Medicinal Product Statistics (drug utilization). Definitions for all covariates are provided in Supplemental Table 3. A detailed description of the various registers is provided in the supplementary material.
2.3. Exposure definition Episodes of apixaban, dabigatran, and rivaroxaban treatment were defined to last as long as new overlapping prescriptions were filled. The duration of each filled prescription was defined by the number of tablets in the package and the recommended treatment regimen with standard dose for each drug (i.e. for apixaban, dabigatran, and rivaroxaban, respectively, two, two, and one tablets a day). To avoid gaps in continuous treatment episodes, we allowed a 30-day gap between the last day of the previous prescription and the date of the new prescription.
The propensity score was estimated using a logistic regression model, including as predictors all variables in Table 1. Users of individual DOACs were matched 1:1 on the propensity score to create three pair-wise matched cohorts: apixaban vs. dabigatran, apixaban vs. rivaroxaban, and rivaroxaban vs. dabigatran [30]. Matching was performed using the nearest neighbor algorithm (caliper width 0.2 of the standard deviation of the logit score).
3. Results 3.1. Cohort selection During the study period, we identified a total of 13,957 new users of DOACs with NVAF, of whom 12,638 were eligible for inclusion (4920 apixaban, 3913 dabigatran, and 3805 rivaroxaban [Fig. 1]). Supplemental Table 4 displays the unmatched baseline characteristics for each individual DOAC. After propensity score estimation and matching in a 1:1 ratio, the cohorts used in the analyses of apixaban vs. dabigatran included a total of 6470 participants; apixaban vs. rivaroxaban a total of 7352 participants and rivaroxaban vs. dabigatran included a total of 5440 participants. In each of the matched cohorts, baseline characteristics were well balanced between the groups (Table 1) with standard deviations below 10% and nicely weighted (see Supplemental Table 6). 3.2. Primary outcomes Fig. 2 reports HRs for the primary effectiveness outcome of stroke or systemic embolism and primary safety outcomes of any major bleeding for the three propensity score-matched analyses during one-year follow-up along with incidence curves. The proportional hazard assumption was fulfilled for all primary effectiveness and safety analyses. 3.2.1. Apixaban vs. dabigatran Mean follow-up was 210 days for apixaban and 241 days for dabigatran. For use of apixaban, stroke or systemic embolism occurred with an event rate of 2.36 per 100 person compared with 1.78 per 100 person years for use of dabigatran (HR, 1.27; 95% CI, 0.82–1.96). Major bleeding occurred with an event rate of 2.25 per 100 person years for use of apixaban compared with 2.34 per 100 person years for use of dabigatran (HR, 0.94; 95% CI, 0.62–1.41). During use of apixaban, death from any cause occurred with an event rate of 3.19 per 100 person years compared with 2.79 per 100 person years for use of dabigatran (HR, 1.12; 95% CI, 0.79–1.61). 3.2.2. Apixaban vs. rivaroxaban Mean follow-up was 212 days for apixaban and 201 days for rivaroxaban. Stroke or systemic embolism occurred with an event rate of 3.19 per 100 person years for use of apixaban compared with 2.57 per 100 person years for use of rivaroxaban (HR, 1.25; 95% CI, 0.87–1.79). Major bleeding occurred with an event rate of 3.37 per 100 person years for use of apixaban vs. 3.87 per 100 person years
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
N.W. Andersson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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Table 1 Baseline characteristics of NVAF patients in propensity-score matched cohorts of apixaban and dabigatran, apixaban and rivaroxaban, and rivaroxaban and dabigatran, in 1:1 ratio. Values are numbers (percentages) unless stated otherwise. Propensity-score-matched cohorts Characteristics Demographics Male sex Age, mean (SD) Place of birth: Denmark Place of birth: Rest of Europe Place of birth: Outside Europe Place of birth: Missing Calendar yeara Year: 2012–13 Year: 2014–16 Medical history Ischemic heart disease Heart failure/cardiomyopathy Hospital contact with hypertension Ischemic stroke or transient ischemic attackb Venous thromboembolic disorders Arterial disease Other arrythmia Liver disease including venous disorders Renal disease Chronic lung disease Rheumatic disease Peptic ulcer/esophageal disorder Cancer History of intracranial bleeding History of gastrointestinal bleeding History of other serious bleeding Alcohol abuse Prescription drug use ARB/ACE-I Calcium channel blockers Loop diuretics Other diuretics Beta-blockers Anti-arrythmics classes I and III Digoxin Nitrates Platelet inhibitors Anemia treatment Lipid lowering drugs Oral antidiabetic drugs Insulin Antidepressants Anxiolytics, hypnotics and sedatives Pulmonary inhalants Oral corticosteroids NSAIDs Opiates Paracetamol Systemic hormone replacement therapy Anti-osteoporotic drugs Drugs for peptic ulcer/gastroesophageal reflux Number of prescription drugs used No. of drugs used: 0–4 No. of drugs used: 5–9 No. of drugs used: 10–14 No. of drugs used: 15+ Days of hospitalization Days of hospitalization: 0 days Days of hospitalization: 1–7 days Days of hospitalization: N7 days Number of outpatient contacts Number of outpatient contacts: 0 Number of outpatient contacts: 1–2 Number of outpatient contacts: N2 Emergency department (ED) visit ED-visit: 0 ED-visit: 1
Apixaban (N = 3235)
Dabigatran (N = 3235)
Apixaban (N = 3676)
Rivaroxaban (N = 3676)
Rivaroxaban (N = 2720)
Dabigatran (N = 2720)
2052 (63) 67.6 (8.2) 3044 (94) 139 (4) 41 (1) 11 (0)
2063 (64) 67.5 (7.3) 3042 (94) 144 (4) 35 (1) 14 (0)
2057 (56) 71.9 (9.1) 3482 (95) 146 (4) 34 (1) 14 (0)
2041 (56) 72.0 (9.8) 3488 (95) 143 (4) 32 (1) 13 (0)
1685 (62) 68.2 (8.2) 2574 (95) 108 (4) 26 (1) 12 (0)
1679 (62) 68.2 (7.3) 2567 (94) 112 (4) 27 (1) 14 (1)
1058 (33) 2177 (67)
2548 (79) 687 (21)
1227 (33) 2449 (67)
1229 (33) 2447 (67)
912 (34) 1808 (66)
2153 (79) 567 (21)
614 (19) 396 (12) 1225 (38) 380 (12) 37 (1) 177 (5) 431 (13) 15 (0) 30 (1) 499 (15) 103 (3) 59 (2) 327 (10) 19 (1) 118 (4) 268 (8) 125 (4)
626 (19) 398 (12) 1211 (37) 413 (13) 45 (1) 181 (6) 447 (14) 13 (0) 33 (1) 491 (15) 116 (4) 68 (2) 318 (10) 20 (1) 123 (4) 273 (8) 113 (3)
686 (19) 418 (11) 1545 (42) 660 (18) 86 (2) 237 (6) 508 (14) 14 (0) 41 (1) 608 (17) 158 (4) 91 (2) 441 (12) 38 (1) 139 (4) 338 (9) 126 (3)
692 (19) 450 (12) 1536 (42) 659 (18) 87 (2) 245 (7) 509 (14) 14 (0) 41 (1) 613 (17) 155 (4) 100 (3) 442 (12) 39 (1) 148 (4) 337 (9) 119 (3)
508 (19) 306 (11) 1021 (38) 337 (12) 36 (1) 150 (6) 383 (14) 11 (0) 30 (1) 411 (15) 100 (4) 58 (2) 285 (10) 13 (0) 92 (3) 228 (8) 98 (4)
512 (19) 322 (12) 1033 (38) 356 (13) 40 (1) 149 (5) 395 (15) 10 (0) 29 (1) 412 (15) 106 (4) 65 (2) 269 (10) 18 (1) 99 (4) 227 (8) 93 (3)
1377 (43) 841 (26) 357 (11) 588 (18) 1134 (35) 68 (2) 103 (3) 129 (4) 1134 (35) 104 (3) 1135 (35) 350 (11) 94 (3) 329 (10) 463 (14) 511 (16) 287 (9) 738 (23) 469 (14) 892 (28) 241 (7) 120 (4) 667 (21)
1369 (42) 852 (26) 361 (11) 586 (18) 1137 (35) 60 (2) 109 (3) 134 (4) 1157 (36) 111 (3) 1151 (36) 347 (11) 95 (3) 344 (11) 474 (15) 514 (16) 279 (9) 766 (24) 483 (15) 913 (28) 227 (7) 123 (4) 653 (20)
1522 (41) 1031 (28) 500 (14) 773 (21) 1329 (36) 67 (2) 172 (5) 203 (6) 1462 (40) 206 (6) 1293 (35) 392 (11) 134 (4) 405 (11) 567 (15) 628 (17) 342 (9) 821 (22) 629 (17) 1334 (36) 267 (7) 220 (6) 876 (24)
1553 (42) 1018 (28) 502 (14) 788 (21) 1349 (37) 61 (2) 164 (4) 193 (5) 1463 (40) 203 (6) 1310 (36) 392 (11) 127 (3) 418 (11) 572 (16) 645 (18) 340 (9) 816 (22) 640 (17) 1343 (37) 263 (7) 209 (6) 879 (24)
1127 (41) 712 (26) 302 (11) 503 (18) 978 (36) 53 (2) 98 (4) 111 (4) 951 (35) 104 (4) 985 (36) 275 (10) 89 (3) 273 (10) 375 (14) 463 (17) 239 (9) 636 (23) 398 (15) 797 (29) 195 (7) 115 (4) 572 (21)
1140 (42) 716 (26) 318 (12) 512 (19) 965 (35) 54 (2) 111 (4) 120 (4) 963 (35) 107 (4) 946 (35) 277 (10) 80 (3) 278 (10) 375 (14) 432 (16) 230 (8) 630 (23) 406 (15) 799 (29) 201 (7) 119 (4) 569 (21)
1325 (41) 1175 (36) 523 (16) 212 (7)
1304 (40) 1183 (37) 511 (16) 237 (7)
1325 (36) 1386 (38) 610 (17) 355 (10)
1314 (36) 1388 (38) 617 (17) 357 (10)
1094 (40) 1017 (37) 404 (15) 205 (8)
1090 (40) 1009 (37) 413 (15) 208 (8)
1016 (31) 1783 (55) 436 (13)
1007 (31) 1769 (55) 459 (14)
1074 (29) 1844 (50) 758 (21)
1072 (29) 1841 (50) 763 (21)
868 (32) 1462 (54) 390 (14)
832 (31) 1468 (54) 420 (15)
584 (18) 1731 (54) 920 (28)
579 (18) 1723 (53) 933 (29)
647 (18) 1904 (52) 1125 (31)
631 (17) 1921 (52) 1124 (31)
509 (19) 1426 (52) 785 (29)
518 (19) 1439 (53) 763 (28)
3193 (99) 42 (1)
3190 (99) 45 (1)
3633 (99) 43 (1)
3628 (99) 48 (1)
2631 (97) 89 (3)
2619 (96) 101 (4)
Supplemental Table 3 provides the specific ICD-10 codes as well as drug ATC-codes for the included characteristics. a Calendar year not included in the propensity-score matching. b Ischemic stroke or transient ischemic attack includes: Cerebral infarction, stroke, transient ischemia attack, cerebral vascular syndromes. ACE-I = angiotensin-converting enzymeinhibitor; ARB = angiotensin-receptor blocker; NSAIDs = non-steroidal anti-inflammatory drugs.
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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Fig. 1. Flowchart of study cohort. aIndividuals with use of multiple anticoagulants were excluded upon defining the cohort of new users of DOACs with a new diagnosis of non-valvular atrial fibrillation (NVAF). bThe total number of excluded individuals does not reflect a sum of the respective exclusion criteria since individuals could be excluded for more than one of the stated reasons.
compared to use of rivaroxaban (HR, 0.88; 95% CI, 0.64–1.22). For use of apixaban, death from any cause occurred with an event rate of 5.66 per 100 person years compared with 8.11 per 100 person years for use of rivaroxaban (HR, 0.71; 95% CI, 0.56–0.89). 3.2.3. Rivaroxaban vs. dabigatran Mean follow-up was 204 days for rivaroxaban and 243 days for dabigatran. During use of rivaroxaban, stroke or systemic embolism occurred with an event rate of 1.91 per 100 person compared with 1.54 per 100 person years for use of dabigatran (HR, 1.17; 95% CI, 0.69–1.96). Major bleeding occurred with an event rate of 3.57 per 100 person years for use of rivaroxaban compared with 2.54 per 100 person years for use of dabigatran (HR, 1.35; 95% CI, 0.91– 2.00). Death from any cause occurred with an event rate of 5.36 per 100 person years during use of rivaroxaban compared with 3.18 per 100 person years for use of dabigatran (HR, 1.61; 95% CI, 1.15–2.26). 3.3. Subgroup analyses and secondary outcomes The HRs for subgroup analyses of primary effectiveness outcome according to age, sex, history of bleeding, or history of stroke or TIA are displayed in Fig. 3A. Fig. 3B shows HRs for subgroup analyses of primary safety outcome according to age, sex, history of bleeding, or history of stroke or TIA. No apparent differences across subgroup could be observed. Subtypes of primary outcomes are reported in Supplemental Tables 7, 8, and 9. 4. Discussion In this nationwide cohort study of patients with NVAF, we found no statistically significant differences in the risk of stroke and systemic embolism or major bleeding comparing apixaban, dabigatran, and rivaroxaban in propensity-matched analyses. This study was designed to examine whether there are differences with respect to effectiveness and safety associated with use of the three different DOACs when examined pair-wise in propensitymatched analyses. Clinical trials and recent meta-analyses report DOACs to have at least comparable efficacy vs. warfarin in terms of stroke prevention along with superior safety profiles in terms of bleeding [8–15,17]. These findings have been replicated in recent observational studies comparing DOACs vs. warfarin [31–36].
In addition, network meta-analyses and observational studies comparing DOACs vs. warfarin, report similar efficacy, but indicate a lower risk of major bleeding with use of apixaban and dabigatran compared with use of rivaroxaban [17–20,36]. The results of our study are in line with these previous findings in terms of the risk of stroke and systemic embolism. Our study did not show statistically significant differences in the risk of major bleeding, with estimates indicating that more than moderate differences can be excluded; however, smaller differences cannot be ruled out. Only few studies have previously compared the effectiveness and safety of the individual DOAC without a comparison vs. warfarin [21,37–39]. Recent publications based on observational data utilizing US insurance databases reported similar effectiveness and safety profiles for the three DOACs, however, with decreased risk of various definitions of major bleeding, associated with both apixaban and dabigatran compared to use of rivaroxaban [21,37,38]. One US study compared dabigatran and rivaroxaban among elderly patients previously diagnosed with NVAF [21]. Another US study investigated the effectiveness and safety of apixaban, dabigatran, and rivaroxaban among patients with NVAF; however, with no distinction made between those with and without previous use of other anticoagulants or with a restriction to patients only receiving standard dose treatment [37,38]. Thus, to our knowledge the present is the first study to compare standard dose treatment with apixaban, dabigatran and rivaroxaban (i.e. without warfarin as an indirect comparator) among patients with a recent diagnosis of NVAF that were treatment naïve to anticoagulants in a design using propensity score matching. With current treatment guidelines recommending a DOAC as first-line anticoagulant therapy for patients with NVAF, the present study contributes with new data from an unselected nationwide cohort based on routine clinical practice bringing further insight into comparative benefits and risks associated with individual DOACs [16]. 4.1. Strengths and limitations We lacked information on e.g. body mass index and smoking that could influence the risk of stroke or bleeding. To reduce the possibility of factors influencing the association, we took into account a wide range of baseline characteristics with use of a comprehensive propensity score model. Of note, although some baseline differences between the treatment groups were present in the unmatched cohorts, such as history of ischemic stroke and TIA, and though the use of register data
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
N.W. Andersson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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Fig. 2. Incidence curves for the primary outcomes. Incidence curves and hazard ratios for the risk of stroke and systemic embolism and major bleeding comparing use of apixaban vs. dabigatran, apixaban vs. rivaroxaban, and rivaroxaban vs. dabigatran during one-year follow-up. CI = Confidence Interval.
might underestimate the frequencies of some potential confounders, the baseline characteristics across the treatment groups were wellbalanced in the respective matched cohorts used for analysis. The study was designed with the main purpose to provide propensitymatched comparisons between DOACs; hence, as such, results from the three cohorts should primarily be interpreted separately. Although causal inference cannot be drawn given the observational design, recent studies that utilized US insurance claims data reported similar estimates [21,37,38]. Additionally, observational studies of clinical effectiveness and safety should be seen as complementary rather than comparable to clinical trials.
In this study, we defined NVAF as a discharge diagnosis of atrial fibrillation/flutter, which has high validity (positive predictive value [PPV] between 92% and 99%) in the Danish National Patient Registry [40–42]. To further increase specificity in terms of identifying individuals with NVAF, we excluded individuals with a previous heart valve disorder or surgical heart valve procedures. Further, a diagnosis of stroke following a diagnosis of atrial fibrillation/flutter in the Danish National Patient Registry has been previously validated with a PPV of 97% [40], but appropriate validation studies are lacking for systemic embolism and for the composite bleeding outcome used in this study. However, to increase specificity of outcome events in general,
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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Fig. 3. Hazard ratios for subgroup analyses of primary effectiveness (3A) and safety (3B) outcomes for use of apixaban vs. dabigatran, apixaban vs. rivaroxaban, and rivaroxaban vs. dabigatran in propensity-matched cohorts of NVAF patientsa. Estimates were similar across the subgroups examined. aNumbers of event and rates are available in Supplemental Tables 7, 8, and 9. bDabigatran served as reference. cRivaroxaban served as reference. CI = Confidence Interval; TIA = transient ischemic attack.
we only included such that lead to inpatient hospitalization i.e. serious events. Ascertainment of DOAC use was based on filled prescriptions and not actual use. Non-adherence to dispensed drugs would bias the results toward no effect and obscure a true effect, if present. It should also be noted that the statistical power to detect differences in some subgroup and secondary analyses was limited; hence, these analyses should be interpreted with caution. The use of population based registers allowed detailed characterization of included patients, minimal loss to follow-up, and independent assessment of exposure as well as outcome throughout the study period. The nationwide coverage means that the results are likely generalizable to similar adult populations. Of note, the new user design excluded patients with previous NVAF diagnoses and previous use of anticoagulants in order to allow more robust comparison and to increase the probability of isolating any differential effectiveness and
safety of each DOAC. We also only included patients treated with standard dose and excluded patients with use of multiple anticoagulants, chronic kidney disease, heart valve disorders, prosthesis or surgery, and recent venous thromboembolism or musculoskeletal surgery. Hence this study cohort represents a subset of patients with NVAF; however, with a strong focus on internal validity.
5. Conclusion In this large cohort study of patients with NVAF from clinical practice we found no overall statistically significant difference of the risk of stroke or systemic embolism or major bleeding examining three different DOACs (apixaban, dabigatran and rivaroxaban) in propensitymatched comparisons. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out.
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
N.W. Andersson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Funding/support and role of funder/sponsor There was no specific funding for this study. Dr. Svanström was supported by grants from Lundbeck Foundation. Dr. Pasternak was supported by an investigator grant from the Strategic Research Area in Epidemiology program at Karolinska Institutet. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Conflicts of interest and financial disclosures The authors have no conflicts of interest to declare.
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Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation☆ Niklas W. Andersson a,⁎, Henrik Svanström a, Marie Lund a, Björn Pasternak a,b, Mads Melbye a,c,d a
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark d Department of Medicine, Stanford University School of Medicine, Stanford, California, USA b c
a r t i c l e
i n f o
Article history: Received 11 September 2017 Received in revised form 15 February 2018 Accepted 9 March 2018 Available online xxxx Keywords: Non-valvular atrial fibrillation Direct oral anticoagulant Stroke Major bleeding Propensity-matched comparison
a b s t r a c t Background: The comparative effectiveness and safety of individual direct oral anticoagulants (DOACs) in clinical practice is largely unknown. The study objectives were to compare effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation (NVAF). Methods: Based on nationwide registers we established a population-based historical cohort study of 12,638 new users of standard dose DOACs (apixaban 5 mg twice daily, dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily) with NVAF in Denmark, July 2013 to March 2016. Patients were matched on propensity scores in a 1:1 ratio comparing apixaban vs. dabigatran (for a total of 6470 patients), apixaban vs. rivaroxaban (7352 patients), and rivaroxaban vs. dabigatran (5440 patients). Hazard ratios (HRs) for stroke or systemic embolism (effectiveness outcome) and major bleeding (safety outcome) were estimated. Results: In propensity-matched comparisons of the risk of stroke or systemic embolism, the HRs were 1.27 (95% confidence interval [CI], 0.82–1.96) for apixaban vs. dabigatran, 1.25 (95% CI, 0.87–1.79) for apixaban vs. rivaroxaban, and 1.17 (95% CI, 0.69–1.96) for rivaroxaban vs. dabigatran. For the risk of major bleeding, the HRs were 0.94 (95% CI, 0.62–1.41) for apixaban vs. dabigatran, 0.88 (95% CI, 0.64–1.22) for apixaban vs. rivaroxaban, and 1.35 (95% CI, 0.91–2.00) for rivaroxaban vs. dabigatran. Conclusions: Among patients with NVAF in routine clinical practice, there were no statistically significant differences in risk of stroke or systemic embolism or major bleeding in propensity-matched comparisons between apixaban, dabigatran, and rivaroxaban used in standard doses. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation is the most common arrhythmia in developed countries and is associated with an up to five-fold increased risk of stroke and with increased mortality [1–4]. Anticoagulants are critical for prevention of stroke, and since the introduction of direct oral anticoagulant (DOAC) drugs their use has become widespread in clinical practice [5–7].
Abbreviations: DOAC, direct oral anticoagulant; NVAF, non-valvular atrial fibrillation; ATC, Anatomic Therapeutic Classification system; ICD-10, International Classification of Diseases version 10; HR, hazard ratio; CI, confidence interval; TIA, transient ischemic attack; PPV, positive predictive value. ☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen, Denmark. E-mail address: [email protected] (N.W. Andersson).
Anticoagulant treatment for stroke prevention should be weighed against the primary concern of an increased risk of bleeding. In clinical trials, the efficacy of DOACs (apixaban, dabigatran, rivaroxaban, and edoxaban) has been shown to be at least non-inferior to warfarin, but with superior safety profiles, mainly due to lower rates of intracranial bleeding [8–17]. To date, however, no head-to-head trials comparing individual DOACs have been published. In network meta-analyses of randomized controlled trials (RCTs), similar rates of stroke and systemic embolism were found for apixaban, dabigatran, and rivaroxaban. Further, there were significantly lower risks of clinically relevant bleeding for apixaban compared to both dabigatran and rivaroxaban and for dabigatran compared to rivaroxaban [17–20]. However, potential heterogeneity in the included study populations and trial methodology might have influenced the validity of these indirect comparisons [8,17]. In the absence of RCTs comparing individual DOACs, observational studies utilizing data from clinical practice can provide means to assess the comparative effectiveness and safety of individual DOACs [20–22]. Given lack of randomization, observational studies are inherently
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Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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susceptible to confounding and other types of bias [23]. Careful attention and study designs that appropriately prioritize internal validity are therefore necessary. In a nationwide cohort study, we investigated the association between use of apixaban, dabigatran, and rivaroxaban and risk of stroke or systemic embolism and major bleeding among patients with non-valvular atrial fibrillation (NVAF).
2.4. Confounder control
2. Methods
2.5. Statistical analyses
2.1. Study design
Follow-up started on the index date and ended on the first instance of an outcome event, death, disappearance, emigration, one year after index date, end of treatment, switch to another DOAC or warfarin, or end of study period (March 31, 2016). All analyses were conducted using Cox proportional hazards regression, estimating hazard ratios (HRs) with 95% confidence intervals (CIs). The proportional hazard assumption was assessed using a Wald test for the interaction between time since index date and treatment. P values were based on Wald tests. All statistical tests were two-sided; CIs that did not overlap 1.0 were considered to indicate statistical significance. Analyses were performed with the use of SAS software 9.4. Subgroup analyses were conducted according to sex, age (≥65 years vs. b65 years), history of stroke or transient ischemic attack (TIA), and history of bleeding. In secondary analyses, we analyzed all-cause mortality along with subtypes of primary effectiveness and safety outcomes as well as fatal primary outcome events. The study was approved by the Danish Data Protection Agency. Ethics approval is not required for register-based research in Denmark.
We conducted a historical register-based cohort study from July 1, 2013 to March 31, 2016. The source population consisted of new users of apixaban, dabigatran, and rivaroxaban, aged 45 years of age or older, with a recent diagnosis of NVAF. The start of the study period was selected to avoid the inclusion of very early users of each of the included DOACs (dabigatran was introduced in Denmark August 2011; rivaroxaban February 2012; and apixaban, December 2012 [24]), who may have been selected individuals [25]. This study was designed with the purpose of maximizing internal validity allowing simpler interpretation and a more robust comparison of cohorts. Firstly, the study was restricted to new users of anticoagulants, with no previous use of any DOACs or warfarin within one year prior to study entry. The new user design reduced the potential influence from previous treatments with the study drugs or factors associated herewith which could otherwise bias the results [26]. Secondly, the study only included patients with a recent diagnosis of NVAF within 90 days prior to start of DOAC treatment to reduce confounding by indication as well as to ensure more similar time points in course of disease (details and International Classification of Diseases [ICD] codes for inclusion in Supplemental Table 1). Thirdly, the study was restricted to patients receiving standard dose treatment of DOAC (apixaban 5 mg twice daily, dabigatran 150 mg twice daily, and rivaroxaban 20 mg once daily) with the intention to reduce the potential for unmeasured confounding. Reduced dose of DOAC are generally prescribed to elderly patients and patients with more advanced comorbidity, such as renal disease, and is likely to be associated with poorer health and frailty; factors that are difficult to capture using register data. Fourth, to further reduce the potential for confounding by indication and unmeasured confounding, we excluded participants who: i) had major musculoskeletal surgery within the last 30 days, ii) had chronic kidney disease (stage 4, 5 or receiving dialysis), iii) had heart valve disorder, prosthesis, or surgical heart valve procedure, or iv) had venous thromboembolism within the last six months (see Supplemental Table 1 for further details). Fifth, propensity score matching was used to take into account a broad range of baseline characteristics that may potentially influence the risk of the outcome. The study included three sets of analyses in separate propensity score-matched cohorts. We estimated the risk of stroke or systemic embolism and major bleeding associated with use of apixaban compared with dabigatran in the first cohort, apixaban vs. rivaroxaban in the second cohort and rivaroxaban vs. dabigatran in the third cohort. The date of the first filled prescription for a DOAC was defined as the study index date. The primary effectiveness outcome was defined as a hospital admission with a primary or secondary diagnosis of stroke or systemic embolism. The primary safety outcome “major bleeding” was defined as a hospital admission with a diagnosis of intracranial bleeding, gastrointestinal bleeding (bleeding ulcer, hematemesis or melena) or other serious bleeding (anemia caused by bleeding, bleeding of unknown origin, bleeding of the respiratory or urinary tract, peritoneal, retinal or orbital bleeding). Outcome definitions are provided in Supplemental Table 2.
2.2. Data sources Individual-level data were linked between different registers using the unique personal identification number assigned to all inhabitants in Denmark. We established the cohort on the basis of records of diagnoses of NVAF obtained from the National Patient Register [27] and information on filled prescriptions of anticoagulants obtained from the Register of Medicinal Product Statistics [27,28]. Information on outcomes was obtained from the National Patient Register. Supplemental Table 1 list all study drugs with ATC (Anatomic Therapeutic Classification system)-codes. Data on potential confounders was obtained from the National Patient Register (medical history), the Danish Civil Registration System (demographic variables) [29] and the Register of Medicinal Product Statistics (drug utilization). Definitions for all covariates are provided in Supplemental Table 3. A detailed description of the various registers is provided in the supplementary material.
2.3. Exposure definition Episodes of apixaban, dabigatran, and rivaroxaban treatment were defined to last as long as new overlapping prescriptions were filled. The duration of each filled prescription was defined by the number of tablets in the package and the recommended treatment regimen with standard dose for each drug (i.e. for apixaban, dabigatran, and rivaroxaban, respectively, two, two, and one tablets a day). To avoid gaps in continuous treatment episodes, we allowed a 30-day gap between the last day of the previous prescription and the date of the new prescription.
The propensity score was estimated using a logistic regression model, including as predictors all variables in Table 1. Users of individual DOACs were matched 1:1 on the propensity score to create three pair-wise matched cohorts: apixaban vs. dabigatran, apixaban vs. rivaroxaban, and rivaroxaban vs. dabigatran [30]. Matching was performed using the nearest neighbor algorithm (caliper width 0.2 of the standard deviation of the logit score).
3. Results 3.1. Cohort selection During the study period, we identified a total of 13,957 new users of DOACs with NVAF, of whom 12,638 were eligible for inclusion (4920 apixaban, 3913 dabigatran, and 3805 rivaroxaban [Fig. 1]). Supplemental Table 4 displays the unmatched baseline characteristics for each individual DOAC. After propensity score estimation and matching in a 1:1 ratio, the cohorts used in the analyses of apixaban vs. dabigatran included a total of 6470 participants; apixaban vs. rivaroxaban a total of 7352 participants and rivaroxaban vs. dabigatran included a total of 5440 participants. In each of the matched cohorts, baseline characteristics were well balanced between the groups (Table 1) with standard deviations below 10% and nicely weighted (see Supplemental Table 6). 3.2. Primary outcomes Fig. 2 reports HRs for the primary effectiveness outcome of stroke or systemic embolism and primary safety outcomes of any major bleeding for the three propensity score-matched analyses during one-year follow-up along with incidence curves. The proportional hazard assumption was fulfilled for all primary effectiveness and safety analyses. 3.2.1. Apixaban vs. dabigatran Mean follow-up was 210 days for apixaban and 241 days for dabigatran. For use of apixaban, stroke or systemic embolism occurred with an event rate of 2.36 per 100 person compared with 1.78 per 100 person years for use of dabigatran (HR, 1.27; 95% CI, 0.82–1.96). Major bleeding occurred with an event rate of 2.25 per 100 person years for use of apixaban compared with 2.34 per 100 person years for use of dabigatran (HR, 0.94; 95% CI, 0.62–1.41). During use of apixaban, death from any cause occurred with an event rate of 3.19 per 100 person years compared with 2.79 per 100 person years for use of dabigatran (HR, 1.12; 95% CI, 0.79–1.61). 3.2.2. Apixaban vs. rivaroxaban Mean follow-up was 212 days for apixaban and 201 days for rivaroxaban. Stroke or systemic embolism occurred with an event rate of 3.19 per 100 person years for use of apixaban compared with 2.57 per 100 person years for use of rivaroxaban (HR, 1.25; 95% CI, 0.87–1.79). Major bleeding occurred with an event rate of 3.37 per 100 person years for use of apixaban vs. 3.87 per 100 person years
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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Table 1 Baseline characteristics of NVAF patients in propensity-score matched cohorts of apixaban and dabigatran, apixaban and rivaroxaban, and rivaroxaban and dabigatran, in 1:1 ratio. Values are numbers (percentages) unless stated otherwise. Propensity-score-matched cohorts Characteristics Demographics Male sex Age, mean (SD) Place of birth: Denmark Place of birth: Rest of Europe Place of birth: Outside Europe Place of birth: Missing Calendar yeara Year: 2012–13 Year: 2014–16 Medical history Ischemic heart disease Heart failure/cardiomyopathy Hospital contact with hypertension Ischemic stroke or transient ischemic attackb Venous thromboembolic disorders Arterial disease Other arrythmia Liver disease including venous disorders Renal disease Chronic lung disease Rheumatic disease Peptic ulcer/esophageal disorder Cancer History of intracranial bleeding History of gastrointestinal bleeding History of other serious bleeding Alcohol abuse Prescription drug use ARB/ACE-I Calcium channel blockers Loop diuretics Other diuretics Beta-blockers Anti-arrythmics classes I and III Digoxin Nitrates Platelet inhibitors Anemia treatment Lipid lowering drugs Oral antidiabetic drugs Insulin Antidepressants Anxiolytics, hypnotics and sedatives Pulmonary inhalants Oral corticosteroids NSAIDs Opiates Paracetamol Systemic hormone replacement therapy Anti-osteoporotic drugs Drugs for peptic ulcer/gastroesophageal reflux Number of prescription drugs used No. of drugs used: 0–4 No. of drugs used: 5–9 No. of drugs used: 10–14 No. of drugs used: 15+ Days of hospitalization Days of hospitalization: 0 days Days of hospitalization: 1–7 days Days of hospitalization: N7 days Number of outpatient contacts Number of outpatient contacts: 0 Number of outpatient contacts: 1–2 Number of outpatient contacts: N2 Emergency department (ED) visit ED-visit: 0 ED-visit: 1
Apixaban (N = 3235)
Dabigatran (N = 3235)
Apixaban (N = 3676)
Rivaroxaban (N = 3676)
Rivaroxaban (N = 2720)
Dabigatran (N = 2720)
2052 (63) 67.6 (8.2) 3044 (94) 139 (4) 41 (1) 11 (0)
2063 (64) 67.5 (7.3) 3042 (94) 144 (4) 35 (1) 14 (0)
2057 (56) 71.9 (9.1) 3482 (95) 146 (4) 34 (1) 14 (0)
2041 (56) 72.0 (9.8) 3488 (95) 143 (4) 32 (1) 13 (0)
1685 (62) 68.2 (8.2) 2574 (95) 108 (4) 26 (1) 12 (0)
1679 (62) 68.2 (7.3) 2567 (94) 112 (4) 27 (1) 14 (1)
1058 (33) 2177 (67)
2548 (79) 687 (21)
1227 (33) 2449 (67)
1229 (33) 2447 (67)
912 (34) 1808 (66)
2153 (79) 567 (21)
614 (19) 396 (12) 1225 (38) 380 (12) 37 (1) 177 (5) 431 (13) 15 (0) 30 (1) 499 (15) 103 (3) 59 (2) 327 (10) 19 (1) 118 (4) 268 (8) 125 (4)
626 (19) 398 (12) 1211 (37) 413 (13) 45 (1) 181 (6) 447 (14) 13 (0) 33 (1) 491 (15) 116 (4) 68 (2) 318 (10) 20 (1) 123 (4) 273 (8) 113 (3)
686 (19) 418 (11) 1545 (42) 660 (18) 86 (2) 237 (6) 508 (14) 14 (0) 41 (1) 608 (17) 158 (4) 91 (2) 441 (12) 38 (1) 139 (4) 338 (9) 126 (3)
692 (19) 450 (12) 1536 (42) 659 (18) 87 (2) 245 (7) 509 (14) 14 (0) 41 (1) 613 (17) 155 (4) 100 (3) 442 (12) 39 (1) 148 (4) 337 (9) 119 (3)
508 (19) 306 (11) 1021 (38) 337 (12) 36 (1) 150 (6) 383 (14) 11 (0) 30 (1) 411 (15) 100 (4) 58 (2) 285 (10) 13 (0) 92 (3) 228 (8) 98 (4)
512 (19) 322 (12) 1033 (38) 356 (13) 40 (1) 149 (5) 395 (15) 10 (0) 29 (1) 412 (15) 106 (4) 65 (2) 269 (10) 18 (1) 99 (4) 227 (8) 93 (3)
1377 (43) 841 (26) 357 (11) 588 (18) 1134 (35) 68 (2) 103 (3) 129 (4) 1134 (35) 104 (3) 1135 (35) 350 (11) 94 (3) 329 (10) 463 (14) 511 (16) 287 (9) 738 (23) 469 (14) 892 (28) 241 (7) 120 (4) 667 (21)
1369 (42) 852 (26) 361 (11) 586 (18) 1137 (35) 60 (2) 109 (3) 134 (4) 1157 (36) 111 (3) 1151 (36) 347 (11) 95 (3) 344 (11) 474 (15) 514 (16) 279 (9) 766 (24) 483 (15) 913 (28) 227 (7) 123 (4) 653 (20)
1522 (41) 1031 (28) 500 (14) 773 (21) 1329 (36) 67 (2) 172 (5) 203 (6) 1462 (40) 206 (6) 1293 (35) 392 (11) 134 (4) 405 (11) 567 (15) 628 (17) 342 (9) 821 (22) 629 (17) 1334 (36) 267 (7) 220 (6) 876 (24)
1553 (42) 1018 (28) 502 (14) 788 (21) 1349 (37) 61 (2) 164 (4) 193 (5) 1463 (40) 203 (6) 1310 (36) 392 (11) 127 (3) 418 (11) 572 (16) 645 (18) 340 (9) 816 (22) 640 (17) 1343 (37) 263 (7) 209 (6) 879 (24)
1127 (41) 712 (26) 302 (11) 503 (18) 978 (36) 53 (2) 98 (4) 111 (4) 951 (35) 104 (4) 985 (36) 275 (10) 89 (3) 273 (10) 375 (14) 463 (17) 239 (9) 636 (23) 398 (15) 797 (29) 195 (7) 115 (4) 572 (21)
1140 (42) 716 (26) 318 (12) 512 (19) 965 (35) 54 (2) 111 (4) 120 (4) 963 (35) 107 (4) 946 (35) 277 (10) 80 (3) 278 (10) 375 (14) 432 (16) 230 (8) 630 (23) 406 (15) 799 (29) 201 (7) 119 (4) 569 (21)
1325 (41) 1175 (36) 523 (16) 212 (7)
1304 (40) 1183 (37) 511 (16) 237 (7)
1325 (36) 1386 (38) 610 (17) 355 (10)
1314 (36) 1388 (38) 617 (17) 357 (10)
1094 (40) 1017 (37) 404 (15) 205 (8)
1090 (40) 1009 (37) 413 (15) 208 (8)
1016 (31) 1783 (55) 436 (13)
1007 (31) 1769 (55) 459 (14)
1074 (29) 1844 (50) 758 (21)
1072 (29) 1841 (50) 763 (21)
868 (32) 1462 (54) 390 (14)
832 (31) 1468 (54) 420 (15)
584 (18) 1731 (54) 920 (28)
579 (18) 1723 (53) 933 (29)
647 (18) 1904 (52) 1125 (31)
631 (17) 1921 (52) 1124 (31)
509 (19) 1426 (52) 785 (29)
518 (19) 1439 (53) 763 (28)
3193 (99) 42 (1)
3190 (99) 45 (1)
3633 (99) 43 (1)
3628 (99) 48 (1)
2631 (97) 89 (3)
2619 (96) 101 (4)
Supplemental Table 3 provides the specific ICD-10 codes as well as drug ATC-codes for the included characteristics. a Calendar year not included in the propensity-score matching. b Ischemic stroke or transient ischemic attack includes: Cerebral infarction, stroke, transient ischemia attack, cerebral vascular syndromes. ACE-I = angiotensin-converting enzymeinhibitor; ARB = angiotensin-receptor blocker; NSAIDs = non-steroidal anti-inflammatory drugs.
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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Fig. 1. Flowchart of study cohort. aIndividuals with use of multiple anticoagulants were excluded upon defining the cohort of new users of DOACs with a new diagnosis of non-valvular atrial fibrillation (NVAF). bThe total number of excluded individuals does not reflect a sum of the respective exclusion criteria since individuals could be excluded for more than one of the stated reasons.
compared to use of rivaroxaban (HR, 0.88; 95% CI, 0.64–1.22). For use of apixaban, death from any cause occurred with an event rate of 5.66 per 100 person years compared with 8.11 per 100 person years for use of rivaroxaban (HR, 0.71; 95% CI, 0.56–0.89). 3.2.3. Rivaroxaban vs. dabigatran Mean follow-up was 204 days for rivaroxaban and 243 days for dabigatran. During use of rivaroxaban, stroke or systemic embolism occurred with an event rate of 1.91 per 100 person compared with 1.54 per 100 person years for use of dabigatran (HR, 1.17; 95% CI, 0.69–1.96). Major bleeding occurred with an event rate of 3.57 per 100 person years for use of rivaroxaban compared with 2.54 per 100 person years for use of dabigatran (HR, 1.35; 95% CI, 0.91– 2.00). Death from any cause occurred with an event rate of 5.36 per 100 person years during use of rivaroxaban compared with 3.18 per 100 person years for use of dabigatran (HR, 1.61; 95% CI, 1.15–2.26). 3.3. Subgroup analyses and secondary outcomes The HRs for subgroup analyses of primary effectiveness outcome according to age, sex, history of bleeding, or history of stroke or TIA are displayed in Fig. 3A. Fig. 3B shows HRs for subgroup analyses of primary safety outcome according to age, sex, history of bleeding, or history of stroke or TIA. No apparent differences across subgroup could be observed. Subtypes of primary outcomes are reported in Supplemental Tables 7, 8, and 9. 4. Discussion In this nationwide cohort study of patients with NVAF, we found no statistically significant differences in the risk of stroke and systemic embolism or major bleeding comparing apixaban, dabigatran, and rivaroxaban in propensity-matched analyses. This study was designed to examine whether there are differences with respect to effectiveness and safety associated with use of the three different DOACs when examined pair-wise in propensitymatched analyses. Clinical trials and recent meta-analyses report DOACs to have at least comparable efficacy vs. warfarin in terms of stroke prevention along with superior safety profiles in terms of bleeding [8–15,17]. These findings have been replicated in recent observational studies comparing DOACs vs. warfarin [31–36].
In addition, network meta-analyses and observational studies comparing DOACs vs. warfarin, report similar efficacy, but indicate a lower risk of major bleeding with use of apixaban and dabigatran compared with use of rivaroxaban [17–20,36]. The results of our study are in line with these previous findings in terms of the risk of stroke and systemic embolism. Our study did not show statistically significant differences in the risk of major bleeding, with estimates indicating that more than moderate differences can be excluded; however, smaller differences cannot be ruled out. Only few studies have previously compared the effectiveness and safety of the individual DOAC without a comparison vs. warfarin [21,37–39]. Recent publications based on observational data utilizing US insurance databases reported similar effectiveness and safety profiles for the three DOACs, however, with decreased risk of various definitions of major bleeding, associated with both apixaban and dabigatran compared to use of rivaroxaban [21,37,38]. One US study compared dabigatran and rivaroxaban among elderly patients previously diagnosed with NVAF [21]. Another US study investigated the effectiveness and safety of apixaban, dabigatran, and rivaroxaban among patients with NVAF; however, with no distinction made between those with and without previous use of other anticoagulants or with a restriction to patients only receiving standard dose treatment [37,38]. Thus, to our knowledge the present is the first study to compare standard dose treatment with apixaban, dabigatran and rivaroxaban (i.e. without warfarin as an indirect comparator) among patients with a recent diagnosis of NVAF that were treatment naïve to anticoagulants in a design using propensity score matching. With current treatment guidelines recommending a DOAC as first-line anticoagulant therapy for patients with NVAF, the present study contributes with new data from an unselected nationwide cohort based on routine clinical practice bringing further insight into comparative benefits and risks associated with individual DOACs [16]. 4.1. Strengths and limitations We lacked information on e.g. body mass index and smoking that could influence the risk of stroke or bleeding. To reduce the possibility of factors influencing the association, we took into account a wide range of baseline characteristics with use of a comprehensive propensity score model. Of note, although some baseline differences between the treatment groups were present in the unmatched cohorts, such as history of ischemic stroke and TIA, and though the use of register data
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
N.W. Andersson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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Fig. 2. Incidence curves for the primary outcomes. Incidence curves and hazard ratios for the risk of stroke and systemic embolism and major bleeding comparing use of apixaban vs. dabigatran, apixaban vs. rivaroxaban, and rivaroxaban vs. dabigatran during one-year follow-up. CI = Confidence Interval.
might underestimate the frequencies of some potential confounders, the baseline characteristics across the treatment groups were wellbalanced in the respective matched cohorts used for analysis. The study was designed with the main purpose to provide propensitymatched comparisons between DOACs; hence, as such, results from the three cohorts should primarily be interpreted separately. Although causal inference cannot be drawn given the observational design, recent studies that utilized US insurance claims data reported similar estimates [21,37,38]. Additionally, observational studies of clinical effectiveness and safety should be seen as complementary rather than comparable to clinical trials.
In this study, we defined NVAF as a discharge diagnosis of atrial fibrillation/flutter, which has high validity (positive predictive value [PPV] between 92% and 99%) in the Danish National Patient Registry [40–42]. To further increase specificity in terms of identifying individuals with NVAF, we excluded individuals with a previous heart valve disorder or surgical heart valve procedures. Further, a diagnosis of stroke following a diagnosis of atrial fibrillation/flutter in the Danish National Patient Registry has been previously validated with a PPV of 97% [40], but appropriate validation studies are lacking for systemic embolism and for the composite bleeding outcome used in this study. However, to increase specificity of outcome events in general,
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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Fig. 3. Hazard ratios for subgroup analyses of primary effectiveness (3A) and safety (3B) outcomes for use of apixaban vs. dabigatran, apixaban vs. rivaroxaban, and rivaroxaban vs. dabigatran in propensity-matched cohorts of NVAF patientsa. Estimates were similar across the subgroups examined. aNumbers of event and rates are available in Supplemental Tables 7, 8, and 9. bDabigatran served as reference. cRivaroxaban served as reference. CI = Confidence Interval; TIA = transient ischemic attack.
we only included such that lead to inpatient hospitalization i.e. serious events. Ascertainment of DOAC use was based on filled prescriptions and not actual use. Non-adherence to dispensed drugs would bias the results toward no effect and obscure a true effect, if present. It should also be noted that the statistical power to detect differences in some subgroup and secondary analyses was limited; hence, these analyses should be interpreted with caution. The use of population based registers allowed detailed characterization of included patients, minimal loss to follow-up, and independent assessment of exposure as well as outcome throughout the study period. The nationwide coverage means that the results are likely generalizable to similar adult populations. Of note, the new user design excluded patients with previous NVAF diagnoses and previous use of anticoagulants in order to allow more robust comparison and to increase the probability of isolating any differential effectiveness and
safety of each DOAC. We also only included patients treated with standard dose and excluded patients with use of multiple anticoagulants, chronic kidney disease, heart valve disorders, prosthesis or surgery, and recent venous thromboembolism or musculoskeletal surgery. Hence this study cohort represents a subset of patients with NVAF; however, with a strong focus on internal validity.
5. Conclusion In this large cohort study of patients with NVAF from clinical practice we found no overall statistically significant difference of the risk of stroke or systemic embolism or major bleeding examining three different DOACs (apixaban, dabigatran and rivaroxaban) in propensitymatched comparisons. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out.
Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047
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Funding/support and role of funder/sponsor There was no specific funding for this study. Dr. Svanström was supported by grants from Lundbeck Foundation. Dr. Pasternak was supported by an investigator grant from the Strategic Research Area in Epidemiology program at Karolinska Institutet. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Conflicts of interest and financial disclosures The authors have no conflicts of interest to declare.
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Please cite this article as: N.W. Andersson, et al., Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.03.047