ABSTRACT
The objective of this study was to investigate the characteristics and trends of therapeutic errors in non‐healthcare facility settings associated with antithrombotic medications reported to United States Poison Centers by analyzing data from the National Poison Data System from 2000 to 2021. There were 57 288 reported therapeutic error‐related exposures involving antithrombotic medications as the primary substance. The rate of therapeutic errors increased by 590.9% during this 22‐year period. Although most (90.1%) therapeutic errors were clinically inconsequential and did not receive treatment at a healthcare facility, 2.3% were medically admitted, and 2.1% experienced a serious medical outcome, including 16 fatalities. Three‐fourths (74.9%) of therapeutic errors were among > 59‐year‐olds, and females represented 58.0% of exposures. Warfarin was the most commonly involved antithrombotic medication (37.5%), followed by direct oral anticoagulants (DOACs, 28.7%) and clopidogrel (23.3%). Therapeutic errors involving warfarin were more likely to be associated with a medical admission (odds ratio [OR] = 2.23; 95% confidence interval [CI]: 1.99–2.49) or a serious medical outcome (OR = 2.99; 95% CI: 2.65–3.37), and DOACs were less likely to be associated with a medical admission (OR = 0.53, 95% CI: 0.46–0.61) or a serious medical outcome (OR = 0.45; 95% CI: 0.38–0.53) than therapeutic errors involving other antithrombotic medications. The rate of therapeutic errors involving warfarin significantly increased by 187.0% during 2000–2011, followed by a 57.6% significant decrease during 2011–2021. The rate of therapeutic errors involving DOACs increased significantly by 1118.2% during 2011–2021. The scenario “inadvertently took/given medication twice” accounted for 56.3% of all therapeutic errors. Increased risk reduction efforts are needed to prevent antithrombotic‐related therapeutic errors.
Keywords: adverse drug events, anticoagulant medication, antiplatelet medication, medication errors, toxicity
Abbreviations
- CCU
critical care unit
- CI
confidence interval
- DOAC
direct oral anticoagulant
- FDA
Food and Drug Administration
- NPDS
National Poison Data System
- OR
odds ratio
- PC
poison center
- US
United States
1. Introduction
Antithrombotic medications include anticoagulant and antiplatelet pharmaceutical agents and are a key strategy for the prevention and treatment of thrombosis and thromboembolism. The use of these medications has important public health benefits because atrial fibrillation‐related thromboembolic events and venous thrombosis and thromboembolism are associated with major morbidity and mortality in the United States (US) and globally [1, 2, 3, 4]. However, antithrombotic medications can cause hemorrhage that may result in serious morbidity or fatality [5, 6, 7, 8]. More than 6 million individuals use anticoagulants in the United States [1, 9], and approximately half of the adverse events associated with anticoagulant use involve therapeutic errors [5, 6].
Previous studies have identified anticoagulants as one of the most common medication groups associated with adverse drug events [10, 11]. These studies include reports from individual hospitals [5], emergency departments [10, 12], nursing homes [13], and multiple countries [14, 15]. Previous research on therapeutic errors has often included all medication groups (not solely antithrombotic medications) [16, 17, 18, 19] or focused on a specific class of antithrombotic medications, such as warfarin, direct oral anticoagulants (DOACs), or heparins [15, 20, 21, 22, 23]. This study contributes to our knowledge of therapeutic errors associated with antithrombotic medications because it includes both anticoagulant and antiplatelet medications, focuses on therapeutic errors occurring outside the healthcare facilities, and analyzes data from a national database over a 22‐year period. The objective of this study was to investigate the characteristics and trends of therapeutic errors in non‐healthcare facility settings associated with antithrombotic medications reported to US Poison Centers (PCs) during 2000–2021.
2. Methods
2.1. Data Sources
Data were obtained from the National Poison Data System (NPDS) regarding exposures involving therapeutic errors related to antithrombotic medications reported to US PCs. The NPDS is the data warehouse for US PCs and is maintained by America's Poison Centers [24, 25]. In addition, US population data were obtained from the US Census Bureau and were used to calculate population‐based exposure rates, including age group‐ and sex‐specific rates [26, 27, 28]. This study was deemed exempt from approval by the Institutional Review Board of the Research Institute at Nationwide Children's Hospital.
2.2. Case Selection Criteria
This study included exposures reported to US PCs from January 1, 2000, through December 31, 2021, related to therapeutic errors involving antithrombotic medications that occurred at locations outside a healthcare facility. Non‐healthcare facility exposures were identified by excluding all exposures with an exposure site coded by PC personnel as “healthcare facility.” [29] The NPDS defines a therapeutic error as “an unintentional deviation from a proper therapeutic regimen that results in the wrong dose, incorrect route of administration, administration to the wrong person, or administration of the wrong substance.” [29] Cases were provided by America's Poison Centers using NPDS generic and product codes for anticoagulant and antiplatelet medications. The NPDS defines a generic code as “a code that represents a broad group of related products” and a product code as “a code specific to the exact substance or product by brand name, concentration, and formulation.” A generic code “allows for groupings of related product codes (each product code is assigned to only one generic code).” [29] Acetylsalicylic acid was not included in this study (other than as aspirin/omeprazole combination products under the “other antiplatelet medications” category) because it is widely used for purposes other than its antiplatelet aggregation properties, including as an analgesic, anti‐inflammatory, or antipyretic agent. Cases were excluded from the study if they had a medical outcome of “confirmed non‐exposure” (n = 367) or “unrelated effect” (n = 2504). In addition, America's Poison Centers determines a “relative contribution to fatality” for substances associated with reported deaths, and we excluded two cases in which antithrombotic medications were judged to be “probably not responsible” for the fatality.
2.3. Study Variables
Variables in this study included the year when the incident occurred, sex, age group (< 20, 20–49, 50–59, 60–69, 70–79, and > 79 years), type of exposure (single‐ or multiple‐substance exposure), and type of therapeutic error. In addition, antithrombotic medication categories in this study included: (1) warfarin (excluding rodenticides), (2) heparins (including both low molecular weight and unfractionated heparin), (3) DOACs (including direct thrombin inhibitor [dabigatran] and the factor Xa inhibitors), (4) clopidogrel, (5) other antiplatelet medications (including aspirin/omeprazole, cangrelor, cilostazol, prasugrel, ticagrelor, glycoprotein IIb/IIIa inhibitors, but excluding clopidogrel), (6) other anticoagulant medications (excluding DOACs), and (7) unknown type of antithrombotic medications. Based on NPDS product codes, America's Poison Centers separated (1) DOACs from other types of anticoagulants and (2) clopidogrel from other types of antiplatelet medications, and these categories were provided to us in the study dataset. Although DOACs do not have their own generic code, individual DOAC medications have a product code, and the earliest DOAC product code (for dabigatran) was established in the NPDS at the end of 2010; therefore, exposures related to DOACs in this study only included the Years 2011 through 2021.
Medical outcomes were based on NPDS categories [29], which included (1) no effect, (2) minor effect (minimally bothersome symptoms that generally resolve rapidly with no residual disability), (3) moderate effect (more pronounced, prolonged, or systemic than minor symptoms), (4) major effect (symptoms are life‐threatening or result in significant disability or disfigurement), (5) death, (6) not followed (includes minimal clinical effects possible and judged as a nontoxic exposure), and (7) unable to follow (judged as a potentially toxic exposure). During analyses, “unable to follow” was considered as “unknown,” and moderate effect, major effect, and death were grouped into the category “serious medical outcome.”
The highest level of health care received was based on NPDS categories [29], which included (1) no treatment received at a healthcare facility, (2) treated/evaluated and released from a healthcare facility, (3) admitted to a critical care unit (CCU), (4) admitted to a non‐CCU, (5) admitted to a psychiatric facility, (6) patient refused referral/did not arrive at a healthcare facility, and (7) unknown (which includes lost to follow‐up, left against medical advice, and unknown). Cases with the management site coded as “unknown” were included in the unknown category for highest level of health care received. During analyses, “admitted to a CCU” and “admitted to a non‐CCU” were combined into a single category representing medical admissions.
2.4. Statistical Analysis
Data were analyzed using IBM SPSS 28.0 (IBM Corporation, Armonk, NY) and SAS 9.4 (SAS Institute Inc., Cary, NC). All data analyses, except those involving trends over time, were limited to exposures involving an antithrombotic medication as the primary substance. A primary substance is the substance that is most likely responsible for the observed clinical effects, as determined by a specialist in poison information at the reporting PC. Both single‐ and multiple‐substance exposures, for which an antithrombotic medication was considered the primary substance, were included in these analyses. Trends over time were analyzed using all reported exposures involving antithrombotic medication‐related therapeutic errors (including both primary and non‐primary substance exposures). Simple or piecewise linear regression analyses were performed, as appropriate, to determine the statistical significance of trends by evaluating whether the null hypothesis of slope = 0 could be rejected at a significance level of α = 0.05 using Student's t‐test. Breakpoints for piecewise analyses were identified using scatter plots. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to determine the magnitude of association of various factors with (1) medical admission (i.e., admission to a CCU or non‐CCU), (2) serious medical outcome, or (3) fatality.
3. Results
3.1. General Characteristics
There were 57 288 therapeutic error‐related exposures in non‐healthcare facility settings involving antithrombotic medications as the primary substance reported to US PCs from 2000 through 2021. Most (90.1%) exposures did not receive treatment at a healthcare facility, whereas 6.8% were treated/evaluated and released, and 2.3% were medically admitted (Table 1). Most (78.4%) reported exposures were not followed because they were considered to have only minimal clinical effects or were judged to be a nontoxic exposure, whereas 17.4% experienced no effect, and 2.1% experienced a serious medical outcome. Females accounted for more than half (58.0%) of exposures.
TABLE 1.
Characteristics of therapeutic errors associated with antithrombotic medications as the primary substance reported to United States Poison Centers by age group, National Poison Data System 2000–2021.
| Characteristics | Age groups | Unknown, n | Total | |||||
|---|---|---|---|---|---|---|---|---|
| < 20 years | 20–49 years | 50–59 years | 60–69 years | 70–79 years | > 79 years | |||
| n (%) a | n (%) a | n (%) a | n (%) a | n (%) a | n (%) a | n (%) a | ||
| Sex | ||||||||
| Male | 872 (60.7) | 2397 (42.9) | 2869 (46.9) | 4989 (45.4) | 6026 (40.5) | 4830 (36.2) | 2033 | 24 016 (42.0) |
| Female | 564 (39.3) | 3192 (57.1) | 3244 (53.1) | 5990 (54.6) | 8842 (59.5) | 8498 (63.8) | 2872 | 33 202 (58.0) |
| Unknown | 1 | 6 | 3 | 4 | 3 | 4 | 49 | 70 |
| Type of exposure | ||||||||
| Single‐substance | 1288 (89.6) | 4676 (83.6) | 4781 (78.2) | 8650 (78.8) | 11 642 (78.3) | 10 004 (75.0) | 4232 | 45 273 (79.0) |
| Multiple‐substance | 149 (10.4) | 919 (16.4) | 1335 (21.8) | 2333 (21.2) | 3229 (21.7) | 3328 (25.0) | 722 | 12 015 (21.0) |
| Highest level of health care received | ||||||||
| No treatment received in an HCF | 1092 (79.0) | 4692 (87.4) | 5255 (89.2) | 9623 (90.1) | 13 168 (91.0) | 11 586 (89.6) | 4567 | 49 983 (90.1) |
| Treated/evaluated and released | 210 (15.2) | 478 (8.9) | 432 (7.3) | 744 (7.0) | 867 (6.0) | 921 (7.1) | 99 | 3751 (6.8) |
| Admitted to a HCF | 73 (5.3) | 150 (2.8) | 145 (2.5) | 229 (2.1) | 350 (2.4) | 336 (2.6) | 17 | 1300 (2.3) |
| CCU | 27 (2.0) | 40 (0.8) | 35 (0.6) | 76 (0.7) | 114 (0.8) | 101 (0.8) | 4 | 397 (0.7) |
| Non‐CCU | 46 (3.3) | 107 (2.0) | 108 (1.8) | 150 (1.4) | 235 (1.6) | 235 (1.8) | 12 | 893 (1.6) |
| Psychiatric facility | 0 (0.0) | 3 (0.1) | 2 (0.0) | 3 (0.0) | 1 (0.0) | 0 (0.0) | 1 | 10 (0.0) |
| Patient refused referral/did not arrive at HCF | 8 (0.6) | 47 (0.9) | 61 (1.0) | 87 (0.8) | 80 (0.6) | 93 (0.7) | 42 | 418 (0.8) |
| Unknown b | 54 | 228 | 223 | 300 | 406 | 396 | 229 | 1836 |
| Medical outcome | ||||||||
| No effect | 377 (27.1) | 944 (17.5) | 1004 (16.9) | 1867 (17.4) | 2655 (18.2) | 2340 (18.0) | 536 | 9723 (17.4) |
| Minor effect | 39 (2.8) | 151 (2.8) | 162 (2.7) | 234 (2.2) | 290 (2.0) | 256 (2.0) | 42 | 1174 (2.1) |
| Serious medical outcome c | 39 (2.8) | 147 (2.7) | 124 (2.1) | 227 (2.1) | 299 (2.1) | 288 (2.2) | 23 | 1147 (2.1) |
| Moderate effect | 33 (2.4) | 131 (2.4) | 114 (1.9) | 202 (1.9) | 258 (1.8) | 253 (2.0) | 21 | 1012 (1.8) |
| Major effect | 6 (0.4) | 16 (0.3) | 10 (0.2) | 20 (0.2) | 35 (0.2) | 30 (0.2) | 2 | 119 (0.2) |
| Death | 0 (0.0) | 0 (0.0) | 0 (0.0) | 5 (0.1) | 6 (0.0) | 5 (0.0) | 0 | 16 (0.0) |
| Not followed d | 936 (67.3) | 4162 (77.0) | 4648 (78.3) | 8408 (78.3) | 11 345 (77.8) | 10 113 (77.8) | 4133 | 43 745 (78.4) |
| Unable to follow e | 46 | 191 | 178 | 247 | 282 | 335 | 220 | 1499 |
| Anticoagulant drug category | ||||||||
| Warfarin (excluding rodenticides) | 650 (45.2) | 2341 (41.8) | 2238 (36.6) | 3793 (34.5) | 5240 (35.2) | 5482 (41.1) | 1753 | 21 497 (37.5) |
| Direct oral anticoagulants (DOACs) | 171 (11.9) | 1423 (25.4) | 1320 (21.6) | 3044 (27.7) | 4850 (32.6) | 4223 (31.7) | 1415 | 16 446 (28.7) |
| Clopidogrel | 301 (21.0) | 927 (16.6) | 1690 (27.6) | 2950 (26.9) | 3495 (23.5) | 2771 (20.8) | 1202 | 13 336 (23.3) |
| Heparins | 205 (14.3) | 444 (7.9) | 230 (3.8) | 235 (2.1) | 196 (1.3) | 125 (0.9) | 182 | 1617 (2.8) |
| Other anticoagulant medications | 14 (1.0) | 48 (0.9) | 63 (1.0) | 120 (1.1) | 200 (1.3) | 181 (1.4) | 69 | 695 (1.2) |
| Other antiplatelet medications | 95 (6.6) | 411 (7.3) | 574 (9.4) | 839 (7.6) | 888 (6.0) | 549 (4.1) | 331 | 3687 (6.4) |
| Unknown | 1 | 1 | 1 | 2 | 2 | 1 | 2 | 10 |
| Total (row %) f | 1437 (2.8) | 5595 (10.7) | 6116 (11.7) | 10 983 (21.0) | 14 871 (28.4) | 13 332 (25.5) | 4954 | 57 288 (100.0) |
Abbreviations: CCU, critical care unit; HCF, healthcare facility.
Column percentages may not sum to 100.0% due to rounding errors.
Unknown = Patient lost to follow‐up, left against medical advice, or unknown.
Serious medical outcome is a category that combines the categories of moderate effect, major effect, and death.
Not followed (includes minimal clinical effects possible and judged as a nontoxic exposure).
Unable to follow (judged as a potentially toxic exposure).
Row percentages do not add to 100.0% due to rounding errors.
Three‐fourths (74.9%) of therapeutic error‐related exposures were among individuals > 59 years old; however, these individuals were less likely to experience a medical admission (OR: 0.83; 95% CI: 0.73–0.94) or a serious medical outcome (OR = 0.87; 95% CI: 0.76–0.99) than younger individuals. Conversely, the age group < 20 years old represented 2.8% of exposures and was more likely to experience a medical admission (OR: 2.23; 95% CI: 1.75–2.85) than older individuals. Although 79.0% of < 20‐year‐olds did not receive treatment in a healthcare facility, this was a lower percentage than older age groups. Individuals < 20 years old also experienced “no effect” more commonly (27.1%) than older individuals. In addition, they had a greater proportion of exposures related to heparins (14.3%) and a lower proportion related to DOACs (11.9%) than older individuals. Multiple‐substance exposures accounted for 21.0% of exposures among all age groups, and they were more likely to be associated with a serious medical outcome (OR: 1.49; 95% CI: 1.31–1.71) or a medical admission (OR: 1.17; 95% CI: 1.03–1.33) than single‐substance exposures.
There were 16 fatalities associated with antithrombotic‐related therapeutic errors, including 5 (31.2%) among individuals 60–69 years old, 6 (37.5%) among 70–79‐year‐olds, and 5 (31.2%) among individuals > 79 years old (Table 1). Eleven (68.8%) deaths were single‐substance exposures, and 11 (68.8%) occurred among females. Most fatalities were attributable to either warfarin (31.3%, n = 5) or DOACs (31.3%, n = 5), followed by heparins (25.0%, n = 4), clopidogrel (6.3%, n = 1), and other types of anticoagulants (6.3%, n = 1) (Table 2). Heparin‐related therapeutic errors were more likely to be associated with death (OR: 11.91; 95% CI: 3.84–36.96) than other non‐heparin antithrombotic medications. The relative contribution to fatality of the antithrombotic medication was determined by America's Poison Centers to be undoubtedly responsible in 3 (18.8%) cases, probably responsible in 4 (25.0%), contributory in 2 (12.5%), and unknown in 7 (43.8%) cases.
TABLE 2.
Medical outcome of therapeutic errors associated with antithrombotic medications as the primary substance reported to United States Poison Centers by medication category, National Poison Data System 2000–2021.
| Medical outcome | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Medication category | No effect | Minor effect | Moderate effect | Major effect | Death | Serious medical outcomes b | Not followed c | Unable to follow d | Total |
| n (%) a | n (%) a | n (%) a | n (%) a | n (%) a | n (%) a | n (%) a | n | n (%) a | |
| Warfarin (excluding rodenticides) | 3292 (33.9) | 468 (39.9) | 635 (62.8) | 85 (71.4) | 5 (31.3) | 725 (63.2) | 16 178 (37.0) | 834 | 21 497 (37.5) |
| Direct oral anticoagulants (DOACs) | 2964 (30.5) | 266 (22.7) | 155 (15.3) | 19 (16.0) | 5 (31.3) | 179 (15.6) | 12 721 (29.1) | 316 | 16 446 (28.7) |
| Clopidogrel | 2278 (23.4) | 237 (20.2) | 86 (8.5) | 4 (3.4) | 1 (6.3) | 91 (7.9) | 10 556 (24.1) | 174 | 13 336 (23.3) |
| Heparins | 350 (3.6) | 48 (4.1) | 75 (7.4) | 8 (6.7) | 4 (25.0) | 87 (7.6) | 1038 (2.4) | 94 | 1617 (2.8) |
| Other anticoagulant medications | 121 (1.2) | 12 (1.0) | 8 (0.8) | 1 (0.8) | 1 (6.3) | 10 (0.9) | 537 (1.2) | 15 | 695 (1.2) |
| Other antiplatelet medications | 718 (7.4) | 143 (12.2) | 53 (5.2) | 2 (1.7) | 0 (0.0) | 55 (4.8) | 2706 (6.2) | 65 | 3687 (6.4) |
| Unknown | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 1 | 10 |
| Total (row %) e | 9723 (17.4) | 1174 (2.1) | 1012 (1.8) | 119 (0.2) | 16 (0.0) | 1147 (2.1) | 43 745 (78.4) | 1499 | 57 288 (100.0) |
Column percentages may not sum to 100.0% because of rounding errors.
Serious medical outcome includes moderate effect, major effect, and death.
Not followed (includes minimal clinical effects possible and judged as a nontoxic exposure).
Unable to follow (judged as a potentially toxic exposure).
Row percentages may not sum to 100.0% because of rounding errors.
3.2. Medication Category
Warfarin was the medication category most commonly associated with antithrombotic medication‐related therapeutic errors (37.5%), followed by DOACs (28.7%) and clopidogrel (23.3%) (Table 1). Warfarin also accounted for 63.2% of serious medical outcomes in this study (Table 2). Therapeutic errors involving warfarin were more likely to be associated with a medical admission (OR: 2.23; 95% CI: 1.99–2.49) or a serious medical outcome (OR: 2.99; 95% CI: 2.65–3.37) compared to those involving other non‐warfarin antithrombotic medications. Similarly, therapeutic errors involving heparins were more likely to be associated with a medical admission (OR: 5.20; 95% CI: 4.35–6.21) or a serious medical outcome (OR: 3.04; 95% CI: 2.42–3.81) compared to those involving other non‐heparin antithrombotic medications. Conversely, therapeutic errors involving DOACs were less likely to be associated with a medical admission (OR: 0.53; 95% CI: 0.46–0.61) or a serious medical outcome (OR: 0.45; 95% CI: 0.38–0.53) compared to those involving other non‐DOAC antithrombotic medications. Likewise, clopidogrel‐related therapeutic errors were less likely to be associated with a medical admission (OR: 0.22; 95% CI: 0.18–0.28) or a serious medical outcome (OR: 0.27; 95% CI: 0.22–0.34) compared to those involving other non‐clopidogrel antithrombotic medications.
3.3. Therapeutic Error Scenarios
The most common therapeutic error scenarios were “inadvertently took/given medication twice” (56.3%), followed by “medication doses given/taken too close together” (13.0%), “other incorrect dose” (10.7%), “wrong medication taken/given” (9.7%), and “inadvertently took/given someone else's medication” (6.2%) (Appendix 1). The relative proportions of scenarios were similar among all age groups, except < 20‐year‐olds. Among individuals < 20 years old, “inadvertently took/given someone else's medication” was the most common scenario (38.3%), followed by “wrong medication taken/given” (26.9%) and “inadvertently took/given medication twice” (12.4%). In contrast, “medication doses given/taken too close together” (3.0%) and “other incorrect dose” (7.7%) were less common among < 20‐year‐olds than among older age groups.
3.4. Trends
Trend analyses were performed using population‐based rates that included all 88 097 therapeutic error exposures involving antithrombotic medications, regardless of whether the antithrombotic medication was judged to be the primary substance. The rate of antithrombotic medication‐related therapeutic errors per 100 000 US population increased by 590.9% from 0.33 in 2000 to 2.29 in 2021 (p < 0.0001). Males and females demonstrated similar trends, with a higher rate for females that increased faster than that for males during the study period (Appendix 2). The rate of therapeutic errors increased with increasing age groups, and the older age groups experienced the greatest increases during the study period. The rate of therapeutic errors per 100 000 US population was highest among individuals > 79 years old and increased by 576.4% from 2.33 in 2000 to 15.76 in 2021 (p < 0.0001), followed by 70–79‐year‐olds (424.6% increase from 1.67 in 2000 to 8.76 in 2021, p < 0.0001) and 60–69‐year‐olds (337.9% increase from 0.87 in 2000 to 3.81 in 2021, p < 0.0001) (Figure 1). The rate of antithrombotic medication‐related therapeutic errors associated with a serious medical outcome increased by 400.0% from 0.02 in 2000 to 0.10 in 2021 (p < 0.0001) and the rate of medical admission increased by 800.0% from 0.01 in 2000 to 0.09 in 2021 (p < 0.0001) (Appendix 3).
FIGURE 1.
Annual rate of therapeutic errors involving antithrombotic medications reported to United States Poison Centers by age group, National Poison Data System 2000–2021.
The rate of therapeutic errors per 100 000 US population involving warfarin increased by 187.0% from 0.23 in 2000 to 0.66 in 2011 (p < 0.0001), followed by a 57.6% decrease to 0.28 in 2021 (p < 0.0001) (Figure 2). The rate of therapeutic errors involving clopidogrel increased by 600.0% from 0.07 in 2000 to 0.49 in 2010 (p < 0.0001), followed by a 12.2% decrease to 0.43 in 2021 (p = 0.0032). Exposures to DOACs were first reported in the NPDS in 2011, and the rate of therapeutic errors associated with these medications increased rapidly by 1118.2% from 0.11 in 2011 to 1.34 in 2021 (p < 0.0001).
FIGURE 2.
Annual rate of therapeutic errors involving antithrombotic medications reported to United States Poison Centers by medication category, National Poison Data System 2000–2021.
The rate per 100 000 US population of warfarin‐related therapeutic errors associated with a serious medical outcome increased by 200.0% from 0.01 in 2000 to 0.03 in 2010 (p < 0.0001), followed by a 33.3% decrease to 0.02 in 2021 (p = 0.0011) (Appendix 4). Similarly, the rate of therapeutic error‐related medical admissions associated with warfarin increased by 200.0% from 0.01 in 2000 to 0.03 in 2010 (p < 0.0001), followed by a 33.3% decrease to 0.02 in 2021 (p = 0.0096) (Appendix 5). The rate of clopidogrel‐related therapeutic errors associated with a serious medical outcome increased by 900.0% from 0.002 in 2000 to 0.02 in 2021 (p < 0.0001). Likewise, the rate of therapeutic error‐related medical admissions associated with clopidogrel increased by 900.0% from 0.002 in 2000 to 0.02 in 2021 (p < 0.0001). The rate of DOAC–related therapeutic errors associated with a serious medical outcome increased by 2900.0% from 0.002 in 2011 to 0.06 in 2021 (p < 0.0001). Similarly, the rate of therapeutic error‐related medical admissions associated with DOACs increased by 1566.7% from 0.003 in 2011 to 0.05 in 2021 (p < 0.0001). The rates of heparin‐related therapeutic errors associated with a serious medical outcome (p = 0.4605) or a medical admission (p = 0.6585) did not change significantly during the study period (Appendices 4 and 5).
4. Discussion
Most (90%) antithrombotic medication‐related therapeutic errors occurring outside the healthcare facilities reported to US PCs did not receive treatment at a healthcare facility because the exposure was judged to be clinically minor or inconsequential. However, approximately 2% of individuals were medically admitted, and 2% experienced a serious medical outcome, including 16 fatalities in this study. The rate of antithrombotic medication‐related therapeutic errors increased by > 590% from 2000 to 2021. This increase was driven by the increases associated with warfarin and clopidogrel during 2000–2011, followed by a rapid increase associated with DOACs during 2011–2021, even as the rate for warfarin decreased during this latter period. The increasing trend in therapeutic errors parallels the increased use of anticoagulants in the United States during the study period, especially DOACs [30, 31]. There was a 30% increase in Medicare Part D and Medicaid claims associated with anticoagulants from 2014 to 2019 [30], and the rate of anticoagulant use among patients with atrial fibrillation increased from 56% to 65% during 2011–2020 in a large US study, with DOACs driving the trends and increasingly replacing warfarin [31].
Females had a higher rate of antithrombotic medication‐related therapeutic errors reported to US PCs throughout the study period, with a widening gap during those years compared with the rate for males. This finding was unexpected because previous research has shown that females are less likely to be prescribed anticoagulants [32] and to better adhere to DOAC regimens than males [33]. It is unclear whether this represents a true difference in antithrombotic medication‐related therapeutic error risk or reporting bias to PCs. Previous studies have revealed a female predominance among reports of therapeutic errors to US PCs [16, 17].
Individuals < 20 years old were twice as likely to experience a medical admission than older individuals. This may be related to the different types of therapeutic error scenarios that occurred in this age group. “Inadvertently took/given someone else's medication” and “wrong medication taken/given” accounted for two‐thirds of therapeutic errors among < 20‐year‐olds, whereas “inadvertently took/given medication twice” accounted for most therapeutic errors among individuals 20 years and older. Compared with older individuals, < 20‐year‐olds also had a higher proportion of therapeutic errors associated with heparins, which were associated with higher rates of a serious medical outcome, including death, than other non‐heparin antithrombotic medications. Other factors that may have contributed to higher proportions of medical admissions among younger individuals include medication dose and age‐related bias in admission decisions, which were not assessed in this study.
Since its approval by the US Food and Drug Administration (FDA) in 1954, warfarin, a Vitamin K antagonist, has been the standard of care for preventing and treating thromboembolic events associated with venous thromboembolism and atrial fibrillation [2, 34]. However, warfarin has a relatively narrow therapeutic window and requires routine monitoring with frequent international normalized ratio testing and dietary restrictions [2, 35, 36, 37, 38]. In this study, warfarin accounted for 38% of therapeutic errors and 63% of serious medical outcomes. Therapeutic errors involving warfarin were more than twice as likely to be associated with medical admission to a healthcare facility and three times more likely to be associated with a serious medical outcome compared to those involving other antithrombotic medications. This is consistent with previous studies demonstrating warfarin's frequent association with adverse drug events [5, 39, 40, 41].
Unfractionated and low molecular weight heparins have been commonly prescribed since their FDA approval in 1939 and 1993, respectively [42, 43, 44]. Unlike warfarin, low molecular weight heparin does not require routine monitoring [42], but it can still cause excessive bleeding with inappropriate dosing [45]. In this study, heparins accounted for only 3% of therapeutic errors but were more than five times as likely to be associated with a medical admission, three times as likely to be associated with a serious medical outcome, and almost 12 times as likely to be associated with death compared with other antithrombotic medications. These findings support those of previous research demonstrating the association of heparins with serious adverse drug events [5, 21]. Individuals receiving heparins in this study may have been a higher‐risk population.
Beginning in 2010, the FDA approved a number of DOACs, including the direct thrombin inhibitor dabigatran (2010) and the factor Xa inhibitors rivaroxaban (2011), apixaban (2012), and edoxaban (2015) [38, 46]. DOAC–related therapeutic errors first appeared in our study dataset in 2011, after the NPDS began adding product codes for these medications, and the rate of these therapeutic errors increased rapidly by > 1100% during 2011–2021. This trend was likely driven by increased prescribing and use of DOACs, as well as increased adoption of new DOAC product codes by PCs [30, 31]. DOACs accounted for 29% of therapeutic errors but only 16% of serious medical outcomes in our study. Therapeutic errors involving DOACs were half as likely to be associated with a medical admission or a serious medical outcome as those involving other antithrombotic medications. This is consistent with the evidence supporting an overall superior safety profile for DOACs compared with warfarin [47].
Clopidogrel, a platelet antiaggregating agent approved by the FDA in 1997 [48], accounted for 23% of therapeutic errors in this study but only 8% of serious medical outcomes. Clopidogrel‐related therapeutic errors were one‐fourth as likely to be associated with a medical admission or a serious medical outcome compared to those involving other antithrombotic medications. The rate of therapeutic errors involving clopidogrel increased by 600% during 2000–2010, followed by a 12% decrease during 2010–2021. The decrease was, in part, attributable to a drop in clopidogrel prescriptions in the United States, which decreased by 32.8% from 24.9 million in 2013 to 16.7 million in 2021 based on data from the Medical Expenditure Panel Survey [49]. The rate of clopidogrel‐related therapeutic errors in our study decreased by 8.5% during this same period. This trend may have been influenced by the results of the Dual Antiplatelet Therapy trial published in late 2014, which failed to show a benefit for long‐term use of clopidogrel on the risk of death among patients with, or at risk for, heart disease [50, 51].
The most frequent therapeutic error scenario in this study was “inadvertently took/given medication twice,” which accounted for 56% of reported exposures. This agrees with previous research that showed that this was the most common scenario for therapeutic errors for all pharmaceutical substances combined [16]. Among individuals < 20 years old, “inadvertently took/given someone else's medication” was the most common scenario (38.3%), followed by “wrong medication taken/given” (26.9%). This is likely attributable to the higher prevalence of venous thromboembolism and atrial fibrillation among older age groups, which means that antithrombotic medication‐related therapeutic errors among < 20‐year‐olds are more likely to be events involving medications not prescribed for them.
Therapeutic error risk reduction strategies for the out‐of‐hospital setting include establishing a medication management service program for patients that monitors dosing and provides education regarding appropriate antithrombotic medication use [11]. Additional approaches to mitigate the leading types of therapeutic errors seen in our study include the use of child‐resistant pill organizers and record‐keeping systems that track medication administration [18, 52]. Use of unit‐dose packaging may offer advantages but can be difficult to use for some older adults, which may decrease medication adherence in that population [53].
4.1. Study Limitations
Several limitations exist in this study. This study underestimates the frequency of antithrombotic medication‐related therapeutic errors in non‐healthcare facility settings because not all of these exposures are reported to PCs. In addition, because NPDS data are passively received, reporting bias may exist, with more serious exposures being more likely to be reported. Furthermore, because exposures are self‐reported, PCs and America's Poison Centers cannot fully verify the accuracy of the data obtained. A medication exposure does not necessarily mean that a poisoning or overdose occurred. Medication dose and underlying diagnoses and comorbidities were not accounted for in study analyses. Although the age group < 20 years old comprised < 3% of exposures in this study, it represents an age group that varies dramatically in body weight, physiologically, and with respect to who administers the medication. Given the heterogeneity of this age group, findings among < 20‐year‐olds in this study should be interpreted with caution. Despite established data protocols, miscoding may occur. Mis‐categorization may occur in multiple‐substance exposures when determining which substance is the primary substance. Despite its limitations, the NPDS provides an excellent national database for epidemiologic investigations of therapeutic errors.
5. Conclusions
The rate of antithrombotic medication‐related therapeutic errors occurring outside the healthcare facilities and reported to US PCs increased by > 590% from 2000 to 2021. Although most therapeutic errors were clinically inconsequential, 2% of individuals were medically admitted, and 2% experienced a serious medical outcome, including 16 fatalities. Increased risk reduction efforts are needed to prevent antithrombotic medication‐related therapeutic errors.
Ethics Statement
This study was judged to be exempt from review by the Institutional Review Board of the Research Institute at Nationwide Children's Hospital.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors have nothing to report.
Appendix 1. Top 10 Therapeutic Error Scenarios Involving Antithrombotic Medications as the Primary Substance Reported to United States Poison Centers, National Poison Data System 2000–2021
| Scenarios | Total |
|---|---|
| n (%) a | |
| Inadvertently took/given medication twice | 32 233 (56.3) |
| Medication doses given/taken too close together | 7446 (13.0) |
| Other incorrect dose | 6153 (10.7) |
| Wrong medication taken/given | 5556 (9.7) |
| Inadvertently took/given someone else's medication | 3536 (6.2) |
| Other/unknown therapeutic error | 2387 (4.2) |
| Health professional/iatrogenic error (pharmacist/nurse) | 744 (1.3) |
| Incorrect formulation or concentration given | 594 (1.0) |
| Patient confused or mentally incompetent | 442 (0.8) |
| Confused units of measure | 426 (0.7) |
Column percentages were calculated by dividing the number of times a scenario was associated with a case by the number of cases with at least one scenario (n = 57 266; 22 cases did not have a scenario listed). Percentages will not sum to 100.0% because some cases had more than one reported scenario, and not all scenarios are included in the table.
Appendix 2. Annual Rate of Therapeutic Errors Involving Antithrombotic Medications Reported to United States Poison Centers by Sex, National Poison Data System 2000–2021
Appendix 3. Annual Rate of Therapeutic Errors Involving Antithrombotic Medications Reported to United States Poison Centers Associated With a Serious Medical Outcome or Medical Admission, National Poison Data System 2000–2021
Appendix 4. Annual Rate of Therapeutic Errors Involving Antithrombotic Medications Reported to United States Poison Centers Associated With a Serious Medical Outcome by Medication Category, National Poison Data System 2000–2021
Appendix 5. Annual Rate of Therapeutic Errors Involving Antithrombotic Medications Reported to United States Poison Centers Associated With Medical Admission by Medication Category, National Poison Data System 2000–2021
Funding: The authors gratefully acknowledge the student research scholarship provided by the Child Injury Prevention Alliance to the first‐listed author while she worked on this study. The funding organization did not have any involvement in study design; data collection, analysis, or interpretation; writing of the manuscript; or the decision to submit the manuscript for publication. The interpretations and conclusions expressed in this article do not necessarily represent those of the funding organization.
Data Availability Statement
Data analyzed in this study were from the National Poison Data System, which is a proprietary database owned and managed by America's Poison Centers. Data requests should be submitted to America's Poison Centers.
References
- 1. Barnes G. D., Lucas E., Alexander G. C., and Goldberger Z. D., “National Trends in Ambulatory Oral Anticoagulant Use,” American Journal of Medicine 128, no. 12 (2015): 1300–1305.e2, 10.1016/j.amjmed.2015.05.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Barr D. and Epps Q. J., “Direct Oral Anticoagulants: A Review of Common Medication Errors,” Journal of Thrombosis and Thrombolysis 47, no. 1 (2019): 146–154, 10.1007/s11239-018-1752-9. [DOI] [PubMed] [Google Scholar]
- 3. Chugh S. S., Havmoeller R., Narayanan K., et al., “Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease 2010 Study,” Circulation 129, no. 8 (2014): 837–847, 10.1161/CIRCULATIONAHA.113.005119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Weller S. C., Porterfield L., Davis J. W., Wilkinson G. S., Chen L., and Baillargeon J., “Incidence of Venous Thrombotic Events and Events of Special Interest in a Retrospective Cohort of Commercially Insured US Patients,” BMJ Open 12, no. 2 (2022): e054669, 10.1136/bmjopen-2021-054669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Piazza G., Nguyen T. N., Cios D., et al., “Anticoagulation‐Associated Adverse Drug Events,” American Journal of Medicine 124, no. 12 (2011): 1136–1142, 10.1016/j.amjmed.2011.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Rahmanzade R., Cabrera Diaz F., Zaugg C., Schuetz P., and Salili A. R., “Therapeutic Duplication of Anticoagulants: A Retrospective Study of Frequency and Consequences in a Tertiary Referral Hospital,” Thrombosis Journal 18 (2020): 14, 10.1186/s12959-020-00227-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Shoeb M. and Fang M. C., “Assessing Bleeding Risk in Patients Taking Anticoagulants,” Journal of Thrombosis and Thrombolysis 35, no. 3 (2013): 312–319, 10.1007/s11239-013-0899-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Tran E., Duckett A., Fisher S., and Bohm N., “Appropriateness of Direct Oral Anticoagulant Dosing for Venous Thromboembolism Treatment,” Journal of Thrombosis and Thrombolysis 43, no. 4 (2017): 505–513, 10.1007/s11239-017-1487-z. [DOI] [PubMed] [Google Scholar]
- 9. Tomaselli G. F., Mahaffey K. W., Cuker A., et al., “2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants,” Journal of the American College of Cardiology 70, no. 24 (2017): 3042–3067, 10.1016/j.jacc.2017.09.1085. [DOI] [PubMed] [Google Scholar]
- 10. Budnitz D. S., Shehab N., Lovegrove M. C., Geller A. I., Lind J. N., and Pollock D. A., “US Emergency Department Visits Attributed to Medication Harms, 2017‐2019,” Journal of the American Medical Association 326, no. 13 (2021): 1299–1309, 10.1001/jama.2021.13844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Andreica I. and Grissinger M., “Oral Anticoagulants: A Review of Common Errors and Risk Reduction Strategies,” Pennsylvania Patient Safety Advisory 12, no. 2 (2015): 54–61. [Google Scholar]
- 12. Budnitz D. S., Pollock D. A., Weidenbach K. N., Mendelsohn A. B., Schroeder T. J., and Annest J. L., “National Surveillance of Emergency Department Visits for Outpatient Adverse Drug Events,” Journal of the American Medical Association 296, no. 15 (2006): 1858–1866, 10.1001/jama.296.15.1858. [DOI] [PubMed] [Google Scholar]
- 13. Desai R. J., Williams C. E., Greene S. B., Pierson S., and Hansen R. A., “Anticoagulant Medication Errors in Nursing Homes: Characteristics, Causes, Outcomes, and Association With Patient Harm,” Journal of Healthcare Risk Management 33, no. 1 (2013): 33–43, 10.1002/jhrm.21116. [DOI] [PubMed] [Google Scholar]
- 14. Henriksen J. N., Nielsen L. P., Hellebek A., and Poulsen B. K., “Medication Errors Involving Anticoagulants: Data From the Danish Patient Safety Database,” Pharmacology Research & Perspectives 5, no. 3 (2017): e00307, 10.1002/prp2.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Narum S., Solhaug V., Myhr K., Johansen P. W., Brørs O., and Kringen M. K., “Warfarin‐Associated Bleeding Events and Concomitant Use of Potentially Interacting Medicines Reported to the Norwegian Spontaneous Reporting System,” British Journal of Clinical Pharmacology 71, no. 2 (2011): 254–262, 10.1111/j.1365-2125.2010.03827.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Brophy T. J., Spiller H. A., Casavant M. J., Chounthirath T., Smith M. D., and Xiang H., “Medication Errors Reported to US Poison Control Centers, 2000‐2012,” Clinical Toxicology 52, no. 8 (2014): 880–888, 10.3109/15563650.2014.953168. [DOI] [PubMed] [Google Scholar]
- 17. Hayes B. D., Klein‐Schwartz W., and Gonzales L. F., “Causes of Therapeutic Errors in Older Adults: Evaluation of National Poison Center Data,” Journal of the American Geriatrics Society 57, no. 4 (2009): 653–658, 10.1111/j.1532-5415.2008.02166.x. [DOI] [PubMed] [Google Scholar]
- 18. Hodges N. L., Spiller H. A., Casavant M. J., Chounthirath T., and Smith G. A., “Non‐Health Care Facility Medication Errors Resulting in Serious Medical Outcomes,” Clinical Toxicology 56, no. 1 (2018): 43–50, 10.1080/15563650.2017.1337908. [DOI] [PubMed] [Google Scholar]
- 19. Shah K. and Barker K. A., “Out‐Of‐Hospital Medication Errors: A 6‐Year Analysis of the National Poison Data System,” Pharmacoepidemiology and Drug Safety 18, no. 11 (2009): 1080–1085. [DOI] [PubMed] [Google Scholar]
- 20. Conway S. E., Schaeffer S. E., and Harrison D. L., “Evaluation of Dabigatran Exposures Reported to Poison Control Centers,” Annals of Pharmacotherapy 48, no. 3 (2014): 354–360, 10.1177/1060028013513883. [DOI] [PubMed] [Google Scholar]
- 21. Grissinger M. C., Hicks R. W., Keroack M. A., Marella W. M., and Vaida A. J., “Harmful Medication Errors Involving Unfractionated and Low‐Molecular‐Weight Heparin in Three Patient Safety Reporting Programs,” Joint Commission Journal on Quality and Patient Safety 36, no. 5 (2010): 195–202, 10.1016/s1553-7250(10)36032-6. [DOI] [PubMed] [Google Scholar]
- 22. Spiller H. A., Mowry J. B., Aleguas A. J., et al., “An Observational Study of the Factor Xa Inhibitors Rivaroxaban and Apixaban as Reported to Eight Poison Centers,” Annals of Emergency Medicine 67, no. 2 (2016): 189–195, 10.1016/j.annemergmed.2015.07.014. [DOI] [PubMed] [Google Scholar]
- 23. Stevenson J. W., Minns A. B., Smollin C., et al., “An Observational Case Series of Dabigatran and Rivaroxaban Exposures Reported to a Poison Control System,” American Journal of Emergency Medicine 32, no. 9 (2014): 1077–1084, 10.1016/j.ajem.2014.04.031. [DOI] [PubMed] [Google Scholar]
- 24. America's Poison Centers , “National Poison Data System,” Updated December 18, 2023. Accessed June 14, 2024, https://www.aapcc.org/national‐poison‐data‐system.
- 25. Gummin D. D., Mowry J. B., Beuhler M. C., et al., “2022 Annual Report of the National Poison Data System (NPDS) From America's Poison Centers: 40th Annual Report,” Clinical Toxicology 61, no. 10 (2023): 717–939, 10.1080/15563650.2023.2268981. [DOI] [PubMed] [Google Scholar]
- 26. US Census Bureau , “Intercensal Estimates of the Resident Population by Single Year of Age, Sex, Race, and Hispanic Origin for the United States: April 1, 2000 to July 1, 2010,” Updated October 8, 2021. Accessed August 29, 2024, https://www.census.gov/data/datasets/time‐series/demo/popest/intercensal‐2000‐2010‐national.html.
- 27. US Census Bureau , “Annual Estimates of the Resident Population by Single Year of Age and Sex for the United States: April 1, 2010 to July 1, 2020,” Updated October 8, 2021. Accessed August 29, 2024, https://www.census.gov/programs‐surveys/popest/technical‐documentation/research/evaluation‐estimates/2020‐evaluation‐estimates/2010s‐national‐detail.html.
- 28. US Census Bureau , “Annual Estimates of the Resident Population by Single Year of Age and Sex for the United States: April 1, 2020 to July 1, 2022,” Updated June 25, 2024. Accessed August 29, 2024, https://www.census.gov/data/tables/time‐series/demo/popest/2020s‐national‐detail.html.
- 29. America's Poison Centers , “NPDS Coding Users' Manual,” Updated March 21, 2023. Accessed August 29, 2024, https://www.npds.us/Help/NPDS%20Coding%20User%20Manual%20(June%202023).pdf.
- 30. Duvalyan A., Pandey A., Vaduganathan M., et al., “Trends in Anticoagulation Prescription Spending Among Medicare Part D and Medicaid Beneficiaries Between 2014 and 2019,” Journal of the American Heart Association 10, no. 24 (2021): e022644, 10.1161/jaha.121.022644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Navar A. M., Kolkailah A. A., Overton R., et al., “Trends in Oral Anticoagulant Use Among 436 864 Patients With Atrial Fibrillation in Community Practice, 2011 to 2020,” Journal of the American Heart Association 11, no. 22 (2022): e026723, 10.1161/jaha.122.026723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Lee K. K., Doudesis D., Bing R., et al., “Sex Differences in Oral Anticoagulation Therapy in Patients Hospitalized With Atrial Fibrillation: A Nationwide Cohort Study,” Journal of the American Heart Association 12, no. 5 (2023): e027211, 10.1161/jaha.122.027211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Islam S., Dover D. C., Daniele P., et al., “Sex Differences in the Management of Oral Anticoagulation and Outcomes for Emergency Department Presentation of Incident Atrial Fibrillation,” Annals of Emergency Medicine 80, no. 2 (2022): 97–107, 10.1016/j.annemergmed.2022.03.010. [DOI] [PubMed] [Google Scholar]
- 34. United States Food and Drug Administration , “Coumadin—Highlights of Prescribing Information,” Updated October 2011. Accessed August 29, 2024, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf.
- 35. January C. T., Wann L. S., Alpert J. S., et al., “2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation,” Circulation 130, no. 23 (2014): e199–e267, 10.1161/cir.0000000000000041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Kirchhof P., Benussi S., Kotecha D., et al., “2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS,” European Heart Journal 37, no. 38 (2016): 2893–2962, 10.1093/eurheartj/ehw210. [DOI] [PubMed] [Google Scholar]
- 37. Stevens S. M., Woller S. C., Kreuziger L. B., et al., “Antithrombotic Therapy for VTE Disease,” Chest 160, no. 6 (2021): e545–e608, 10.1016/j.chest.2021.07.055. [DOI] [PubMed] [Google Scholar]
- 38. Zhu J., Alexander G. C., Nazarian S., Segal J. B., and Wu A. W., “Trends and Variation in Oral Anticoagulant Choice in Patients With Atrial Fibrillation, 2010‐2017,” Pharmacotherapy 38, no. 9 (2018): 907–920, 10.1002/phar.2158. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Zaidenstein R., Eyal S., Efrati S., et al., “Adverse Drug Events in Hospitalized Patients Treated With Cardiovascular Drugs and Anticoagulants,” Pharmacoepidemiology and Drug Safety 11, no. 3 (2002): 235–238, 10.1002/pds.693. [DOI] [PubMed] [Google Scholar]
- 40. Classen D. C., Jaser L., and Budnitz D. S., “Adverse Drug Events Among Hospitalized Medicare Patients: Epidemiology and National Estimates From a New Approach to Surveillance,” Joint Commission Journal on Quality and Patient Safety 36, no. 1 (2010): 12–21, 10.1016/s1553-7250(10)36003-x. [DOI] [PubMed] [Google Scholar]
- 41. Fanikos J., Cina J. L., Baroletti S., Fiumara K., Matta L., and Goldhaber S. Z., “Adverse Drug Events in Hospitalized Cardiac Patients,” American Journal of Cardiology 100, no. 9 (2007): 1465–1469, 10.1016/j.amjcard.2007.06.041. [DOI] [PubMed] [Google Scholar]
- 42. Arbit E., Goldberg M., Gomez‐Orellana I., and Majuru S., “Oral Heparin: Status Review,” Thrombosis Journal 4 (2006): 6, 10.1186/1477-9560-4-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. United States Food and Drug Administration , “Heparin Sodium Injection—Highlights of Prescribing Information,” Updated January 2020. Accessed August 29, 2024, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/017037Orig1s187lbl.pdf.
- 44. United States Food and Drug Administration , “Lovenox—Highlights of Prescribing Information,” Updated April 2022. Accessed August 29, 2024, https://products.sanofi.us/lovenox/lovenox.pdf.
- 45. Solari F. and Varacallo M., “Low‐Molecular‐Weight Heparin (LMWH). StatPearls,” Updated August 4, 2023. Accessed August 29, 2024, https://www.ncbi.nlm.nih.gov/books/NBK525957/. [PubMed]
- 46. Chen A., Stecker E., and Warden B. A., “Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges,” Journal of the American Heart Association 9, no. 13 (2020): e017559, 10.1161/jaha.120.017559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Makam R. C. P., Hoaglin D. C., McManus D. D., et al., “Efficacy and Safety of Direct Oral Anticoagulants Approved for Cardiovascular Indications: Systematic Review and Meta‐Analysis,” PLoS One 13, no. 5 (2018): e0197583, 10.1371/journal.pone.0197583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. United States Food and Drug Administration , “Center for Drug Evaluation and Research. Plavix/Clopidogrel Bisulfate Approval Package,” Updated November 17, 1997. Accessed August 29, 2024, https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/20839_Plavix_appltr_prntlbl_medr_chemr_EA_phrmr.pdf.
- 49. Kane S. P., “Clopidogrel, ClinCalc DrugStats Database, Version 2024.08,” Updated August 7, 2024. Accessed September 3, 2024, https://clincalc.com/DrugStats/Drugs/Clopidogrel.
- 50. Mauri L., Kereiakes D. J., Yeh R. W., et al., “DAPT Study Investigators. Twelve or 30 Months of Dual Antiplatelet Therapy After Drug‐Eluting Stents,” New England Journal of Medicine 371, no. 23 (2014): 2155–2166, 10.1056/NEJMoa1409312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. US Food and Drug Administration , “FDA Drug Safety Communication: FDA Review Finds Long‐Term Treatment With Blood‐Thinning Medicine Plavix (Clopidogrel) Does Not Change Risk of Death,” Updated November 6, 2015. Accessed August 27, 2024, https://www.fda.gov/drugs/drug‐safety‐and‐availability/fda‐drug‐safety‐communication‐fda‐review‐finds‐long‐term‐treatment‐blood‐thinning‐medicine‐plavix#:~:text=Safety%20Announcement,at%20risk%20for%2C%20heart%20disease.
- 52. King S. A., Casavant M. J., Spiller H. A., Hodges N. L., Chounthirath T., and Smith G. A., “Pediatric ADHD Medication Exposures Reported to US Poison Control Centers,” Pediatrics 141, no. 6 (2018): e20173872, 10.1542/peds.2017-3872. [DOI] [PubMed] [Google Scholar]
- 53. Conn V. S., Ruppar T. M., Chan K. C., Dunbar‐Jacob J., Pepper G. A., and De Geest S., “Packaging Interventions to Increase Medication Adherence: Systematic Review and Meta‐Analysis,” Current Medical Research and Opinion 31, no. 1 (2015): 145–160, 10.1185/03007995.2014.978939. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data analyzed in this study were from the National Poison Data System, which is a proprietary database owned and managed by America's Poison Centers. Data requests should be submitted to America's Poison Centers.