To address literature gaps on treatment with real-world evidence, this study compared effectiveness, safety, and cost outcomes in NVAF patients with coronary or peripheral artery disease (CAD, PAD) prescribed apixaban versus other oral anticoagulants. NVAF patients aged ≥65 years co-diagnosed with CAD/PAD initiating warfarin, apixaban, dabigatran, or rivaroxaban were selected from the US Medicare population (January 1, 2013 to September 30, 2015). Propensity score matching was used to match apixaban versus warfarin, dabigatran, and rivaroxaban cohorts. Cox models were used to evaluate the risk of stroke/systemic embolism (SE), major bleeding (MB), all-cause mortality, and a composite of stroke/myocardial infarction/all-cause mortality. Generalized linear and two-part models were used to compare stroke/SE, MB, and all-cause costs between cohorts. A total of 33,269 warfarin-apixaban, 9,335 dabigatran-apixaban, and 33,633 rivaroxaban-apixaban pairs were identified after matching. Compared with apixaban, stroke/SE risk was higher in warfarin (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.61 to 2.31), dabigatran (HR: 1.69; 95% CI: 1.18 to 2.43), and rivaroxaban (HR: 1.24; 95% CI: 1.01 to 1.51) patients. MB risk was higher in warfarin (HR: 1.67; 95% CI: 1.52 to 1.83), dabigatran (HR: 1.37; 95% CI: 1.13 to 1.68), and rivaroxaban (HR: 1.87; 95% CI: 1.71 to 2.05) patients vs apixaban. Stroke/SE- and MB-related medical costs per-patient per-month were higher in warfarin, dabigatran, and rivaroxaban patients versus apixaban. Total all-cause health care costs were higher in warfarin and rivaroxaban patients compared with apixaban patients. In conclusion, compared with apixaban, patients on dabigatran, rivaroxaban, or warfarin had a higher risk of stroke/SE, MB, and event-related costs.
Atrial fibrillation (AF) is associated with several complications and comorbidities of considerable clinical and economic concern, which is further exacerbated by comorbidities, such as coronary artery disease (CAD) and peripheral arterial disease (PAD), which are concomitant in 34% to 69% and 4% to 28% of AF diagnosed patients, respectively. Evidence from multiple randomized clinical trials (RCTs) and real-world studies has shown that apixaban was noninferior to warfarin in reducing all-cause mortality, stroke, and major bleeding event rates in patients with nonvalvular AF (NVAF). Further, real-world evidence has shown that use of apixaban in NVAF patients was associated with lower major bleeding event rates when compared with dabigatran and rivaroxaban, similar to lower stroke/systemic embolism (SE) risk, and lower healthcare costs. The performance of direct oral anticoagulants (DOACs) compared to warfarin in patients with concomitant NVAF and CAD or PAD has been evaluated in a previous study. However, there is little research comparing DOACs within a NVAF population with concomitant CAD or PAD. Therefore, this study compared the risk of stroke/SE, major bleeding, mortality, composite outcomes (stroke/myocardial infarction/all-cause mortality), and health care costs among US patients diagnosed with NVAF and CAD or PAD who were newly prescribed apixaban vs warfarin, dabigatran, or rivaroxaban.
Methods
This retrospective observational study used Medicare data from the Centers for Medicare and Medicaid Services. Medicare is a federal health insurance program for people aged ≥65 years, and those with qualifying disabilities, or end-stage renal disease. Over 38 million beneficiaries were enrolled in the fee-for-service Medicare insurance by 2015.
Patients were required to have ≥1 pharmacy claim for warfarin, apixaban, dabigatran, or rivaroxaban between January 1, 2013 and September 30, 2015. The first prescription for an OAC during this period was designated as the index date. Edoxaban was not included in the study given its recent Food and Drug Administration approval in 2015, and hence a small sample size. Further, patients were required to have ≥1 diagnosis of AF and ≥1 diagnosis of CAD or PAD during the 12 months before (baseline period) or on the index date. All patients were aged ≥65 on the index date and had continuous medical and pharmacy health plan enrollment during the baseline period. Exclusion criteria are listed in Figure 1 .
Patient data were assessed from the day after the index date until the earliest of discontinuation, treatment switch, death, study end, medical/pharmacy disenrollment, or 1 year from the index date. Discontinuation was defined as no evidence of index OAC prescription for 30 days from the last day of the last filled prescription days’ supply. A switch was defined as the presence of a nonindex OAC prescription claim within ±30 days of the last days’ supply.
Clinical outcomes were stroke/SE, major bleeding, all-cause mortality, and stroke/myocardial infarction/all-cause mortality. Outcomes were determined using primary diagnoses on discharge records from hospitalizations. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes used to identify stroke/SE (ischemic stroke, hemorrhagic stroke, and SE) and major bleeding (gastrointestinal bleeding, intracranial hemorrhage, and other major bleeding sites) were based on validated administrative-claim based algorithms and can be found in S1 Table. , Death was obtained by validated Social Security records that included the date of death.
Total all-cause health care costs were defined as the sum of medical and pharmacy costs. All-cause medical costs included inpatient, outpatient/ER, and other costs (durable medical equipment, skilled nursing facility, home health agency, and hospice). Stroke/SE-related medical costs were defined as hospitalization costs associated with the first stroke/SE event plus all subsequent stroke/SE costs occurring in the inpatient or outpatient setting (primary and secondary diagnoses). Major bleeding-related medical costs were defined as hospitalization costs associated with the first major bleeding event plus all subsequent bleeding costs occurring in the inpatient or outpatient (primary and secondary diagnoses) setting. Costs included all paid amounts, including Medicare payments, copayments, and deductibles incurred during the follow-up period.
Propensity scores were used to obtain estimates of the average treatment effect using a logistic model with two treatment cohorts. Each patient in the reference cohort (apixaban) was matched with a patient in the comparison cohort (warfarin, dabigatran, or rivaroxaban) using nearest neighbor matching with a caliper of 0.01 without replacement. The included covariates are noted in Table 1 and were considered balanced between the treatment groups if the absolute standardized difference of the mean was ≤10.
| Apixaban cohort | Warfarin cohort | Apixaban cohort | Dabigatran cohort | Apixaban cohort | Rivaroxaban cohort | ||||
|---|---|---|---|---|---|---|---|---|---|
| N = 33,269 | N = 33, 269 | N = 9,335 | N = 9,335 | N = 33,633 | N = 33,633 | ||||
| N(%), Mean (SD) | N(%), Mean (SD) | Std Difference | N(%), Mean (SD) | N(%), Mean (SD) | Std Difference | N(%), Mean (SD) | N(%), Mean(SD) | Std Difference | |
| Age (years) | 78.9 (7.4) | 78.9 (7.4) | 0.07 | 78.1 (7.3) | 77.7 (7.1) | 5.03 | 78.8 (7.4) | 78.7 (7.3) | 1.15 |
| 65-74 | 10,696 (32.2%) | 10,628 (31.9%) | 0.44 | 3,357 (36.0%) | 3,461 (37.1%) | 2.31 | 11,013 (32.7%) | 10,901 (32.4%) | 0.71 |
| 75-79 | 7,296 (21.9%) | 7,330 (22.0%) | 0.25 | 2,287 (24.5%) | 2,288 (24.5%) | 0.02 | 7,433 (22.1%) | 7,412 (22.0%) | 0.15 |
| ≥80 | 15,277 (45.9%) | 15,311 (46.0%) | 0.21 | 3,691 (39.5%) | 3,586 (38.4%) | 2.31 | 15,187 (45.2%) | 15,320 (45.6%) | 0.79 |
| Gender | |||||||||
| Male | 17,910 (53.8%) | 17,931 (53.9%) | 0.13 | 5,144 (55.1%) | 5,236 (56.1%) | 1.98 | 18,178 (54.0%) | 18,131 (53.9%) | 0.28 |
| Female | 15,359 (46.2%) | 15,338 (46.1%) | 0.13 | 4,191 (44.9%) | 4,099 (43.9%) | 1.98 | 15,455 (46.0%) | 15,502 (46.1%) | 0.28 |
| Race | |||||||||
| White | 30,261 (91.0%) | 30,283 (91.0%) | 0.23 | 8,391 (89.9%) | 8,390 (89.9%) | 0.04 | 30,603 (91.0%) | 30,632 (91.1%) | 0.30 |
| Black | 1,516 (4.6%) | 1,511 (4.5%) | 0.07 | 442 (4.7%) | 439 (4.7%) | 0.15 | 1,488 (4.4%) | 1,466 (4.4%) | 0.32 |
| Hispanic | 420 (1.3%) | 401 (1.2%) | 0.52 | 156 (1.7%) | 149 (1.6%) | 0.59 | 424 (1.3%) | 422 (1.3%) | 0.05 |
| Other | 1,072 (3.2%) | 1,074 (3.2%) | 0.03 | 346 (3.7%) | 357 (3.8%) | 0.62 | 1,118 (3.3%) | 1,113 (3.3%) | 0.08 |
| U.S. Geographic Region | |||||||||
| Northeast | 6,496 (19.5%) | 6,415 (19.3%) | 0.62 | 1,834 (19.6%) | 1,888 (20.2%) | 1.45 | 6,423 (19.1%) | 6,414 (19.1%) | 0.07 |
| Midwest | 7,700 (23.1%) | 8,052 (24.2%) | 2.49 | 2,251 (24.1%) | 2,279 (24.4%) | 0.70 | 7,658 (22.8%) | 7,593 (22.6%) | 0.46 |
| South | 14,186 (42.6%) | 14,055 (42.2%) | 0.80 | 3,769 (40.4%) | 3,662 (39.2%) | 2.34 | 14,670 (43.6%) | 14,848 (44.1%) | 1.07 |
| West | 4,866 (14.6%) | 4,726 (14.2%) | 1.20 | 1,468 (15.7%) | 1,496 (16.0%) | 0.82 | 4,861 (14.5%) | 4,760 (14.2%) | 0.86 |
| Other | 21 (0.1%) | 21 (0.1%) | 0.00 | 13 (0.1%) | <11 | 0.92 | 21 (0.1%) | 18 (0.1%) | 0.37 |
| Baseline Comorbidity | |||||||||
| Deyo-Charlson Comorbidity Index | 3.9 (2.6) | 3.9 (2.5) | 0.12 | 3.7 (2.5) | 3.6 (2.5) | 3.92 | 3.8 (2.5) | 3.8 (2.5) | 0.27 |
| CHA 2 DS 2 -VASc Score | 4.4 (1.4) | 4.4 (1.3) | 0.09 | 4.3 (1.4) | 4.2 (1.4) | 2.30 | 4.3 (1.4) | 4.3 (1.4) | 0.65 |
| HAS-BLED Score * | 3.6 (1.2) | 3.6 (1.2) | 1.41 | 3.5 (1.2) | 3.4 (1.2) | 2.00 | 3.6 (1.2) | 3.6 (1.2) | 0.89 |
| Bleeding history | 8,187 (24.6%) | 8,252 (24.8%) | 0.45 | 2,213 (23.7%) | 2,134 (22.9%) | 0.38 | 8,148 (24.2%) | 8,076 (24.0%) | 0.50 |
| Congestive Heart Failure | 12,869 (38.7%) | 12,950 (38.9%) | 0.50 | 3,493 (37.4%) | 3,476 (37.2%) | 0.65 | 12,704 (37.8%) | 12,713 (37.8%) | 0.06 |
| Diabetes Mellitus | 14,667 (44.1%) | 14,712 (44.2%) | 0.27 | 4,191 (44.9%) | 4,221 (45.2%) | 2.39 | 14,661 (43.6%) | 14,668 (43.6%) | 0.04 |
| Hypertension | 31,355 (94.2%) | 31,359 (94.3%) | 0.05 | 8,823 (94.5%) | 8,771 (94.0%) | 4.93 | 31,711 (94.3%) | 31,706 (94.3%) | 0.06 |
| Renal Disease | 9,383 (28.2%) | 9,393 (28.2%) | 0.07 | 2,326 (24.9%) | 2,130 (22.8%) | 1.52 | 9,185 (27.3%) | 9,268 (27.6%) | 0.55 |
| Liver Disease | 1,869 (5.6%) | 1,841 (5.5%) | 0.37 | 550 (5.9%) | 517 (5.5%) | 2.18 | 1,877 (5.6%) | 1,903 (5.7%) | 0.34 |
| Myocardial Infarction | 5,883 (17.7%) | 5,946 (17.9%) | 0.50 | 1,507 (16.1%) | 1,433 (15.4%) | 2.20 | 5,850 (17.4%) | 5,926 (17.6%) | 0.59 |
| Dyspepsia or Stomach Discomfort | 8,179 (24.6%) | 8,109 (24.4%) | 0.49 | 2,221 (23.8%) | 2,134 (22.9%) | 1.05 | 8,223 (24.4%) | 8,260 (24.6%) | 0.26 |
| Stroke/SE | 5,230 (15.7%) | 5,143 (15.5%) | 0.72 | 1,408 (15.1%) | 1,377 (14.8%) | 0.93 | 5,127 (15.2%) | 5,173 (15.4%) | 0.10 |
| Transient ischemic attack | 3,117 (9.4%) | 3,037 (9.1%) | 0.83 | 814 (8.7%) | 822 (8.8%) | 0.30 | 3,133 (9.3%) | 3,163 (9.4%) | 0.38 |
| Anemia and Coagulation Defects | 12,288 (36.9%) | 12,306 (37.0%) | 0.11 | 3,161 (33.9%) | 3,093 (33.1%) | 1.54 | 12,184 (36.2%) | 12,145 (36.1%) | 0.31 |
| Alcoholism | 715 (2.1%) | 684 (2.1%) | 0.65 | 242 (2.6%) | 251 (2.7%) | 0.60 | 719 (2.1%) | 704 (2.1%) | 0.24 |
| PAD only | 4,598 (13.8%) | 4,777 (14.4%) | 1.55 | 1,310 (14.0%) | 1,319 (14.1%) | 0.28 | 4,638 (13.8%) | 4,831 (14.4%) | 1.65 |
| CAD only | 20,242 (60.8%) | 19,844 (59.6%) | 2.44 | 5,721 (61.3%) | 5,805 (62.2%) | 1.85 | 20,571 (61.2%) | 20,348 (60.5%) | 1.36 |
| CAD and PAD | 8,429 (25.3%) | 8,648 (26.0%) | 1.51 | 2,304 (24.7%) | 2,211 (23.7%) | 2.33 | 8,424 (25.0%) | 8,454 (25.1%) | 0.21 |
| Baseline Medication Use | |||||||||
| ACE/ARB | 22,131 (66.5%) | 22,099 (66.4%) | 0.20 | 6,328 (67.8%) | 6,264 (67.0%) | 1.46 | 22,428 (66.7%) | 22,548 (67.0%) | 0.76 |
| Amiodarone | 4,804 (14.4%) | 4,934 (14.8%) | 1.11 | 1,341 (14.4%) | 1,322 (14.2%) | 0.58 | 4,917 (14.6%) | 4,907 (14.6%) | 0.08 |
| Beta Blockers | 21,195 (63.7%) | 21,205 (63.7%) | 0.06 | 5,823 (62.4%) | 5,787 (62.0%) | 0.80 | 21,444 (63.8%) | 21,470 (63.8%) | 0.16 |
| H2-receptor Antagonist | 2,789 (8.4%) | 2,807 (8.4%) | 0.19 | 791 (8.5%) | 757 (8.1%) | 1.32 | 2,798 (8.3%) | 2,794 (8.3%) | 0.04 |
| Proton Pump Inhibitor | 12,016 (36.1%) | 11,798 (35.5%) | 1.37 | 3,212 (34.4%) | 3,239 (34.7%) | 0.61 | 12,199 (36.3%) | 12,244 (36.4%) | 0.28 |
| Statins | 23,995 (72.1%) | 23,961 (72.0%) | 0.23 | 6,556 (70.2%) | 6,473 (69.3%) | 1.94 | 24,319 (72.3%) | 24,472 (72.8%) | 1.02 |
| Anti-platelets | 8,688 (26.1%) | 8,683 (26.1%) | 0.03 | 2,277 (24.4%) | 2,197 (23.5%) | 2.01 | 8,918 (26.5%) | 9,030 (26.8%) | 0.75 |
| NSAIDs | 8,068 (24.3%) | 8,056 (24.2%) | 0.08 | 2,313 (24.8%) | 2,299 (24.6%) | 0.35 | 8,347 (24.8%) | 8,345 (24.8%) | 0.01 |
| Baseline Procedures | |||||||||
| Coronary Bypass surgery | 569 (1.7%) | 639 (1.9%) | 1.58 | 148 (1.6%) | 159 (1.7%) | 0.93 | 561 (1.7%) | 551 (1.6%) | 0.23 |
| Percutaneous Coronary Intervention | 912 (2.7%) | 921 (2.8%) | 0.17 | 251 (2.7%) | 239 (2.6%) | 0.80 | 892 (2.7%) | 915 (2.7%) | 0.42 |
| Index Dose † | |||||||||
| Low Dose | 10,265 (30.9%) | – | – | 2,574 (27.6%) | 2,215 (23.7%) | 8.81 | 10,166 (30.2%) | 13,295 (39.5%) | 0.05 |
| Standard Dose | 23,018 (69.2%) | – | – | 6,763 (72.4%) | 7,123 (76.3%) | 8.84 | 23,481 (69.8%) | 20,422 (60.7%) | 19.19 |
| Baseline All-cause Health Care Costs (PPPM) | |||||||||
| Inpatient Admission Costs | $903 ($1,480) | $1,106 ($1,809) | 12.31 | $879 ($1,491) | $830 ($1,481) | 3.27 | $884 ($1,464) | $995 ($1,612) | 7.26 |
| Outpatient Costs (ER, Office, and other) | $677 ($838) | $659 ($926) | 2.10 | $663 ($824) | $602 ($699) | 8.02 | $676 ($835) | $637 ($822) | 4.67 |
| Prescription Costs | $351 ($613) | $272 ($502) | 14.24 | $350 ($627) | $313 ($432) | 7.05 | $351 ($613) | $333 ($522) | 3.18 |
| Other Costs (DME, SNF, HHA, Hospice) | $342 ($894) | $456 ($1,088) | 11.37 | $323 ($887) | $375 ($987) | 5.45 | $334 ($885) | $415 ($1,054) | 8.31 |
| Total Costs | $2,274 ($2,412) | $2,492 ($2,830) | 8.31 | $2,216 ($2,403) | $2,119 ($2,384) | 4.04 | $2,244 ($2,392) | $2,380 ($2,572) | 5.47 |
| Follow-up Time (Mean) | 183.5 | 227.6 | – | 183.6 | 244.1 | – | 183.9 | 225.2 | – |
| SD | 177.9 | 229.8 | – | 178.4 | 255.1 | – | 178.1 | 234.3 | – |
| 25 th Percentile | 44 | 56 | – | 45 | 30 | – | 44 | 31 | – |
| Median | 120 | 139 | – | 119 | 131 | – | 121 | 132 | – |
| 75 th Percentile | 262 | 330 | – | 265 | 372 | – | 263 | 339 | – |
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