BACKGROUND
Direct-acting oral anticoagulants (DOACs), critical for treating and preventing thrombotic disorders, replaced warfarin as the mainstay of oral anticoagulation therapy due to comparable efficacy, reduced risk of major bleeding, and ease of use. DOAC prescribing among older adults has been increasing in recent years,1 and determining bleeding rates among older adults using DOACs can help guide clinician counseling and prescribing. We used data from a nationally representative surveillance system to describe U.S. emergency department (ED) visits for bleeding among patients aged ≥80 years receiving DOACs.
METHODS
We estimated the number of ED visits for patients aged ≥ 80 years who presented for bleeding while using DOACs from January 1, 2021 to December 31, 2023, using data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance (NEISS-CADES) project, which conducts active surveillance of medication-related harms using a nationally representative, size-stratified probability sample of 82 U.S. hospitals (see Supplementary Text S1 for additional details).2 As previously described, trained abstractors at participating NEISS-CADES hospitals review each ED record to identify medication-related harms based on treating clinicians’ diagnoses.2–4 Sample weights are assigned to each case based on the inverse probability of selection in each stratum, adjusted for nonresponse and hospital non-participation, and post-stratified to adjust for changes in the total number of ED visits annually. NEISS-CADES is a joint collaboration between the U.S. Centers for Disease Control and Prevention (CDC), U.S. Consumer Product Safety Commission, and Food and Drug Administration.
We classified bleeding type hierarchically based on clinical severity.4 The number of unique patients who received at least one prescription for a DOAC during this three-year period was estimated using IQVIA Total Patient Tracker, a nationally projected database based on a 94% sample of U.S. retail pharmacies.3 We calculated national estimates and 95% confidence intervals (CIs) using the SURVEYMEANS procedure in SAS 9.4, accounting for the sample weights and complex sample design. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.5
RESULTS
Based on 7,961 cases in 2021-2023, an estimated annual average of 127,544 ED visits (95% CI, 73,188-181,899) occurred for bleeding among patients aged ≥80 years receiving DOACs, of which 51.1% (95% CI, 45.5%-56.7%) resulted in hospitalization.
Of these ED visits, 44.8% occurred in 2023, mean patient age was 86 years (range, 80-107 years), an estimated 51.4% of patients were female, 65.5% were White persons, and 19.4% had documented concomitant aspirin therapy (Table 1). Body sites involved in bleeding events included gastrointestinal (34.0%), skin or wound (20.7%), genitourinary (16.0%), epistaxis, (14.1%), or central nervous system (4.7%) (Table 2).
Table 1.
Cases and National Estimates of Emergency Department Visits for Bleeding by Adults aged ≥80 Years Receiving Direct-acting Oral Anticoagulants (DOACs), by Case Characteristics—United States, 2021-2023a
| Case Characteristics | Cases | National Estimates of Emergency Department Visits (2021-2023) | ||
|---|---|---|---|---|
|
| ||||
| No. | No. (95% CI) | % (95% CI) | Rate per 100 Recipients of Dispensed Retail DOAC Prescriptionsb (95% CI) | |
| Treatment Year | ||||
|
| ||||
| 2021 | 1,632 | 92,375 (37,862-146,888) | 24.1 (18.2-30.1) | |
| 2022 | 2,539 | 118,790 (69,028-168,552) | 31.0 (28.3-33.7) | |
| 2023 | 3,790 | 171,467 (104,848-238,086) | 44.8 (39.0-50.6) | |
|
| ||||
| Age | ||||
|
| ||||
| 80-84 | 3,279 | 162,586(92,021-233,152) | 42.5(40.4-44.6) | 10.6 (6.0-15.2) |
| ≥85 | 4,682 | 220,045 (126,757-313,332) | 57.5 (55.4-59.6) | 14.6 (8.4-20.7) |
|
| ||||
| DOAC Type c | ||||
|
| ||||
| Apixaban | 5,986 | 287,713 (167,157-408,268) | 75.2 (72.7-77.7) | 12.7 (7.4-18.0) |
| Rivaroxaban | 1,834 | 87,880 (47,640-128,119) | 23.0 (20.7-25.2) | 13.3 (7.2-19.4) |
| Dabigatran | 160 | 8,095 (3,072-13,117)d | 2.1 (1.2-3.0) | 14.9 (5.6-24.1)d |
|
| ||||
| Sex e | ||||
|
| ||||
| Female | 3,865 | 185,703 (101,811-269,595) | 48.5 (44.4-52.6) | 12.2 (7.1-17.3) |
| Male | 4,095 | 196,849 (114,805-278,892) | 51.4 (47.3-55.5) | 14.9 (8.2-21.6) |
|
| ||||
| Race | ||||
|
| ||||
| White | 5,392 | 250,606 (133,787-367,424) | 65.5 (42.6-88.4) | |
| Black or African American | 475 | 16,710 (6,468-26,951)d | 4.4 (1.4-7.4) | |
| Other/Not specified | 2,094 | 115,316 (0-231,907)d | 30.1 (6.6-53.7) | |
|
| ||||
| Concomitant Antithrombotic Agents f | ||||
|
| ||||
| Antiplatelet Agentsg | 1,926 | 96,525 (52,750-140,301) | 25.2 (23.0-27.5) | |
| Aspirin | 1,479 | 74,353 (40,246-108,461) | 19.4 (17.1-21.7) | |
| Other antiplatelet agents | 554 | 27,873 (14,389-41,358) | 7.3 (5.8-8.8) | |
|
| ||||
| Discharge Disposition h | ||||
|
| ||||
| Hospitalized | 4,044 | 195,569 (100,776-290,361) | 51.1 (45.5-56.7) | 6.8 (3.5-10.2) |
| Not Hospitalized | 3,917 | 187,063 (114,171-259,955) | 48.9 (43.3-54.5) | 6.5 (4.0-9.1) |
|
| ||||
| Total | 7,961 | 382,631 (219,565-545,698) | 100 | 13.4 (7.7-19.1) |
Case counts and estimates are from a nationally representative sample of hospitals participating in the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance project, Centers for Disease Control and Prevention. Estimates based on <20 cases or total estimates <1,200 are considered statistically unstable and are not shown. “Direct-acting Oral Anticoagulant” included apixaban, dabigatran, edoxaban, and rivaroxaban.
Estimates of Recipients of Dispensed Retail DOAC Prescriptions are from IQVIA Total Patient Tracker, 2021-2023. Rate obtained by dividing the NEISS-CADES estimate by the corresponding IQVIA Total Patient Tracker estimate.
One case involving edoxaban-related bleeding is not shown.
Estimate has a coefficient of variation >30% and may be statistically unstable.
Sex was not recorded for 1 case.
“Antithrombotic Agents” includes anticoagulants and antiplatelet agents. Not shown: 48 cases involving concurrent use of another anticoagulant (DOAC, warfarin, or low molecular weight heparin).
“Antiplatelet Agents” includes aspirin and other oral antiplatelet agents (e.g., clopidogrel, ticagrelor). Note: because some patients were documented as taking both aspirin and non-aspirin antiplatelet agents, summing individual estimates will exceed the overall estimate for any antiplatelet agent (25.2%).
“Hospitalized” includes hospital admission, observation status admission, or transfer to another facility. “Not Hospitalized” includes treated-and-released and left against medical advice/without being seen.
CI = confidence interval.
Table 2.
National Estimates of Emergency Department Visits for Bleeding by Adults aged ≥80 Years Receiving Direct-acting Oral Anticoagulants (DOACs), by Bleeding Manifestation—United States, 2021-2023a
| Bleeding Manifestationb | National Estimates of Emergency Department Visits (2021-2023) |
|||
|---|---|---|---|---|
| Any Direct-acting Oral Anticoagulant | Apixaban | Rivaroxaban | Dabigatran | |
| 382,631 (219,565-545,698) | 287,713 (167,157-408,268) | 87,880 (47,640-128,119) | 8,095 (3,072-13,117)c | |
| % (95% CI) | % (95% CI) | % (95% CI) | % (95% CI) | |
|
| ||||
| Gastrointestinal bleeding | 34.0 (25.3-42.8) | 33.4 (24.6-42.1) | 34.6 (25.8-43.5) | 50.0 (40.2-59.7) |
| Skin or wound bleeding | 20.7 (13.5-28.0) | 21.3 (14.1-28.5) | 18.9 (11.5-26.4) | 19.4 (6.5-32.4) |
| Genitourinary bleeding | 16.0 (12.1-19.9) | 16.4 (12.0-20.8) | 15.2 (11.5-18.8) | ~ |
| Epistaxis | 14.1 (10.7-17.5) | 13.8 (10.1-17.6) | 15.9 (12.1-19.7) | ~ |
| Central nervous system bleeding | 4.7 (3.3-6.0) | 4.6 (3.3-5.9) | 4.8 (2.6-7.1) | ~ |
| Pulmonary bleeding | 1.6 (1.1-2.1) | 1.4 (0.9-1.9) | 2.0 (1.3-2.7) | ~ |
| Other type of hemorrhage | 8.8 (6.1-11.6) | 9.1 (6.2-11.9) | 8.5 (5.7-11.4) | ~ |
|
| ||||
| Total | 100 | 75.2 (72.7-77.7) | 23.0 (20.7-25.2) | 2.1 (1.2-3.0) |
National estimates are from nationally a representative sample of hospitals participating in the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance project for 2021-2023, Centers for Disease Control and Prevention. Estimates based on <20 cases or total estimates <1,200 are considered statistically unstable and are not shown (~). “Direct-acting Oral Anticoagulant” includes apixaban, dabigatran, edoxaban, and rivaroxaban. 1 case involving edoxaban-related bleeding is not shown.
Bleeding manifestations are mutually exclusive and were assigned hierarchically in the following order based upon presentation severity: central nervous system (includes epidural or subdural hematoma, hemorrhagic stroke, and intracerebral or subarachnoid hemorrhage), pulmonary, gastrointestinal, genitourinary, epistaxis, skin or wound, or other type of hemorrhage.
Estimate has a coefficient of variation >30% and may be statistically unstable.
CI = confidence interval.
For every 100 patients aged ≥80 years dispensed DOACs in 2021-2023, there were an estimated 13.4 ED visits for bleeding (95% CI, 7.7-19.1). The ED visit rate per 100 patients dispensed apixaban was 12.7 (95% CI, 7.4-19.4) and the rate per 100 patients dispensed rivaroxaban was 13.3 (95% CI, 7.2-19.4).
DISCUSSION
These findings highlight the substantial burden of ED visits and hospitalizations for serious bleeding in patients aged ≥80 years receiving DOACs. Nearly one-half of these visits occurred in 2023, signaling the possibility that these events are on the rise, and underscoring the importance of close monitoring of older patients receiving DOACs.
This study has limitations. Given the lack of a comparator group who were not prescribed DOACs, this study does not provide information on the bleeding risk attributable to DOACs in this population, nor does it provide data on the decrease in risk of ED visits due to thrombotic events in older adults prescribed DOACs. These data lack prescribing indication and functional status, as well as the presence of frailty or other comorbid conditions. In addition, the frequency of serious bleeding in patients receiving DOACs is underestimated because only non-fatal events identified in the ED are included, and DOAC dispensing is also underestimated, as long-term care and mail-order prescriptions are not included in IQVIA Total Patient Tracker.
Clinical trials have demonstrated lower rates of major bleeding with DOACs compared with warfarin and an overall efficacy of DOACs in decreasing thrombotic events in patients aged ≥80 years. Nevertheless, this study demonstrates that persistently high rates of serious bleeding with DOACs in older adults remain, and these results can help guide patient education and clinician education efforts. Patients can be provided with accurate information about the risk of serious bleeding when using DOACs, and clinicians can be encouraged to minimize bleeding risk by deprescribing inappropriate antiplatelet therapy and selecting the lowest effective DOAC dose for a particular patient based on indication, age, renal function and body weight.6,7 For clinicians managing DOAC-treated older adults in the ED, risk evaluation (e.g., falls risk assessment) and facilitating patient follow up after ED discharge are key components in mitigating future morbidity in this population.8,9
Supplementary Material
Additional Contributions:
We thank Kathleen O Rose, RN, Sandra K Goring, RN, Veronica Smith, CPC, Arati Baral, MS, and Alex Tocitu, MBA from Chenega Enterprise Systems and Solutions (contractor to CDC) for medical abstraction and programming assistance, as well as Tom Schroeder, MS, Michelle White, Omar Stokes, and data abstractors from the US Consumer Product Safety Commission, for assistance with data acquisition. We thank Jennifer N. Lind Lyles, PharmD, MPH, MBA, of the CDC Division of Healthcare Quality Promotion for her careful review of the manuscript.
Conflict of Interest Statement:
Dr. Cohen reported receiving grants from Consumers Union and The Pew Charitable Trusts and personal fees from UpToDate outside the submitted work. No other disclosures were reported.
Disclaimer:
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Sponsor’s Role:
None. Additionally, no individuals received compensation for their contributions.
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