- Email: [email protected]
Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications
TOXICOLOGY/ORIGINAL RESEARCH
Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications Michael Levine, MD*; Michael C. Beuhler, MD; Anthony Pizon, MD; F. Lee Cantrel, PharmD; Meghan B. Spyres, MD; Frank LoVecchio, DO; Aaron B. Skolnik, MD; Daniel E. Brooks, MD *Corresponding Author. E-mail: [email protected].
Study objective: In recent years, the use of novel anticoagulants and antiplatelet agents has become widespread. Little is known about the toxicity and bleeding risk of these agents after acute overdose. The primary objective of this study is to evaluate the relative risk of all bleeding and major bleeding in patients with acute overdose of novel antiplatelet and anticoagulant medications. Methods: This study is a retrospective study of acute ingestion of apixaban, clopidogrel, ticlopidine, dabigatran, edoxaban, prasugrel, rivaroxaban, and ticagrelor reported to 7 poison control centers in 4 states during a 10-year span. The prevalence of bleeding for each agent was calculated, and hemorrhage was classified as trivial, minor, or major. Results: A total of 322 acute overdoses were identified, with the majority of cases involving clopidogrel (260; 80.7%). Hemorrhage occurred in 16 cases (4.9%), including 7 cases of clopidogrel, 6 cases of rivaroxaban, 2 cases of dabigatran, and 1 case of apixaban. Most cases of hemorrhage were classified as major (n¼9). Comparing the novel anticoagulants with the P2Y12 receptor inhibitors, the relative risk for any bleeding with novel anticoagulant was 6.68 (95% confidence interval 2.63 to 17.1); the relative risk of major bleeding was 18.1 (95% confidence interval 3.85 to 85.0). Conclusion: Acute overdose of novel anticoagulants or antiplatelet agents is associated with a small risk of significant hemorrhage. The risk is greater with the factor Xa inhibitors and direct thrombin inhibitors than with the P2Y12 receptor antagonists. [Ann Emerg Med. 2017;-:1-6.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2017 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2017.08.046
INTRODUCTION Antiplatelet and anticoagulant therapy has undergone a revolutionary change in the past decade. The advent of adenosine diphosphate receptor antagonists and the novel anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) has expanded the options available for prevention and treatment of thromboemboli. At therapeutic dosing, the primary toxicity of the antiplatelet and anticoagulant agents is hemorrhage. This risk may be dose dependent and is increased in patients with advanced age.1,2 However, the risk of bleeding appears to be similar with the direct thrombin inhibitors compared with the factor Xa inhibitors.3 Although it is known from studies on warfarin that patients with acute overdose may develop hemorrhagic complications,4 it is unknown at what rate hemorrhagic complications occur after an acute overdose of the novel anticoagulants or antiplatelet agents. Most of the current literature involving acute overdoses with these agents is limited to case reports.5-16 The majority Volume
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of these describe only minimal or no bleeding. There are also 3 poison control center studies that have been performed.1719 One series reported all calls involving dabigatran and rivaroxaban,17 a separate study examined all calls involving rivaroxaban and apixaban,18 and a third study examined dabigatran ingestions.19 However, these 3 poison control center–based studies were heterogeneous and included all calls involving these agents, not just intentional overdoses. It was hypothesized that the risk of bleeding was greater for the novel anticoagulants compared with nonsalicylatebased antiplatelet agents. Thus, the primary purpose of this study was to evaluate the bleeding risk in patients with acute or acute-on-chronic intentional overdoses with these agents, and to compare the risk of bleeding between the novel anticoagulants with the antiplatelet agents. MATERIALS AND METHODS This retrospective study of poison control center calls involving patients with intentional ingestions of novel Annals of Emergency Medicine 1
Levine et al
Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications
Editor’s Capsule Summary
What is already known on this topic Patients with intentional overdose of antiplatelet and novel anticoagulant medications have an increased risk of hemorrhagic complications. The bleeding risk from various classes of anticoagulant medications is not well characterized. What question this study addressed What is the risk of bleeding after intentional overdose with antiplatelet and novel anticoagulant medications? What this study adds to our knowledge Authors identified 322 cases of intentional overdose during 10 years in 7 US poison center databases. The majority of cases (83.9%) involved antiplatelet agents. Bleeding occurred in 16 cases (4.9%) (7 antiplatelet, 9 novel anticoagulant) and was considered major in 9 cases. How this is relevant to clinical practice Bleeding after overdose with antiplatelet and novel anticoagulant medications is uncommon. Novel anticoagulants carry a greater risk.
antiplatelet or anticoagulant medications was approved by the institutional review board at each of the participating centers. Such cases can include acute and acute-on-chronic ingestions. The data were pooled from 7 poison control centers in 4 states. The primary outcome measurement was the presence of bleeding during the index call or during the follow-up period. A secondary objective was to classify the type of bleeding, should it occur. Setting and Selection of Participants The deidentified data were pooled from 7 poison control centers covering 4 states. These poison control centers collectively receive 670,000 cases yearly and cover a population of 53 million. At each of these centers, the data are entered into commercially available patient management software that collects the same basic data on all patients. This software at each poison control center was queried for all calls between January 1, 2005, and December 31, 2014, for intentional exposures involving the following medications: apixaban, clopidogrel, dabigatran, edoxaban, prasugrel, rivaroxaban, ticagrelor, and ticlopidine. Cases involving drug information without acute exposure, cases involving bleeding while receiving therapeutic dosing, 2 Annals of Emergency Medicine
pediatric (6 years or younger) exploratory ingestions, and accidental double-dose ingestions were excluded. Multiple ingestants were permitted but cases involving warfarin or rodenticides were excluded. Thus, the final data set involved subjects older than 6 years and with intentional ingestions. Data Collection and Processing and Primary Data Analysis Data were collected on predesigned data abstraction sheets and entered into Excel 2010 (version 14.0.7184.5000 Microsoft, Redmond, WA). Data abstraction was performed by a single abstractor at each site. Ten percent of charts were randomly selected by each center, a separate investigator not involved with the original abstraction abstracted those records, and a k statistic was calculated to assess interrater reliability. The individuals performing the data abstraction were aware of the study but not the specific hypothesis being tested. The data abstracted included the implicated agent, demographic information (eg, age, sex), treatment rendered, duration of follow-up, and outcome. The narrative sections of each chart were reviewed to augment data abstraction. If bleeding did occur, the type of bleeding and subsequent interventions were also recorded. Data from each of the centers were pooled. The proportions of bleeding for each agent were calculated, and associated 95% confidence intervals were determined with the Wilson procedure. A 2-tailed analysis was performed. The relative risk of bleeding for novel anticoagulants compared with antiplatelet agents was calculated. All statistical analysis was performed with Stata 2007 (StataCorp, College Station, TX). A k statistic was calculated to assess interrater reliability. Bleeding was classified as major, minor, or trivial, according to previous toxicology literature.20 Major bleeding was defined as fatal bleeding, bleeding associated with hemodynamic instability, bleeding requiring an invasive therapeutic intervention (eg, endoscopy), bleeding requiring the transfusion of one or more units of packed RBCs, or bleeding into an enclosed space (eg, retroperitoneal, intracranial). Minor bleeding was defined as any bleeding resulting in an admission or prolonged observation, but not requiring the administration of packed RBCs or the performance of any invasive procedures. Transfusion of fresh frozen plasma to treat a coagulopathy in the setting of bleeding, without the need to transfuse RBCs, was considered minor bleeding. Trivial bleeding was defined as bleeding not requiring any intervention or prolonged observation, and included persistent oozing from puncture wounds and self-limited bleeding not requiring intervention (eg, epistaxis, hemorrhoidal bleeding). Volume
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Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications
Suturing of self-inflicted laceration without any other intervention was considered trivial. Calls were classified as originating from home or from a hospital. Calls from emergency medical services were classified as originating from home. Successful follow-up was defined as at least one communication with the poison control center at least 4 hours after the index call. RESULTS During the study period, a total of 322 cases were identified (Figure). The median age was 50 years (interquartile range 41 to 59). Men accounted for 207 cases (64.3%). The majority of cases (260; 80.7%) involved clopidogrel. There were 40 cases (12.4%) of rivaroxaban, 9 (2.8%) of dabigatran, 5 (1.6%) of prasugrel, 3 (0.93%) of ticagrelor, and 2 (0.62%) of ticlopidine ingestion that were identified (Table 1). Collectively, antiplatelet agents
accounted for 270 cases (83.9%), whereas the novel anticoagulants accounted for 52 (16%). The k statistic was greater than 0.9 for each variable abstracted. Other statistics were performed as outlined in the “Materials and Methods” section. Overall, bleeding developed in 16 (4.9%) cases, including 7 cases of clopidogrel, 6 cases of rivaroxaban, 2 cases of dabigatran, and 1 case of apixaban. Bleeding was classified as major in 9 cases, minor in 3, and trivial in 4. No cases of hemorrhage were identified with prasugrel, ticagrelor, ticlopidine, or edoxaban. The classification of hemorrhage is presented in Table 2. Details of these 16 patients are presented in Table 3. After overdose, patients ingesting the novel anticoagulants are more likely than those ingesting the antiplatelet agents to develop any bleeding (relative risk 6.68; 95% confidence interval 2.63 to 17.1) and major bleeding (relative risk 18.1; 95% confidence interval 3.85 to 85.0).
1958 total cases idenfied by search
638 cases idenfied and excluded
1320 total remained eligible
990 cases idenfied as accidental double dose or complicaon of therapeuc use
330 Acute adult ingesons
8 with concurrent warfarin or rodencide
322 cases
Figure. Screening population with subsequent exclusion. Volume
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Annals of Emergency Medicine 3
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Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications Table 1. Cases by class and agent. Class
Agent
Antiplatelet P2Y12 inhibitors
Number of Cases (% of Total)
Clopidogrel Prasugrel Ticagrelor Ticlopidine
Anticoagulant Direct thrombin inhibitors Factor Xa inhibitors
260 5 3 2
Dabigatran Rivaroxaban Apixaban Edoxaban
(80.7) (1.6) (0.93) (0.62)
9 (2.8) 40 (12.4) 3 (0.93) 0
LIMITATIONS This study has several limitations. There is no mandatory reporting to poison control centers and calls are often initiated by providers only peripherally involved in the patients’ care. Thus, incomplete or inaccurate information may be provided. In addition, there is a possibility of a selection bias in which only the sickest patients are reported to a poison control center; this would bias the estimated incidence to be higher than expected. Ingestions including multiple substances were included, which could affect the conclusions about attributing the bleeding to the novel antiplatelet and or anticoagulant medications; however, effort was made to exclude other ingestants that are known to cause bleeding. Also, serum confirmation of the ingestion was not performed for these patients, making it impossible to say with certainty that ingestion occurred, only that these are cases of reported ingestion. In this study, follow-up was defined as a call after 4 hours. We assumed a repeated telephone call would be generated to the poison control center. It is possible patients developed bleeding after the last telephone call and the case was not reported. If this happened, the risk of bleeding would be even larger than reported. In this study, Table 2. Incidence of hemorrhage and classification.
Class
Agent
Antiplatelet
Clopidogrel
Anticoagulant
Prasugrel Ticagrelor Ticlopidine Apixaban Dabigatran Rivaroxaban Edoxaban
Classification of Hemorrhage
No. of Cases
Major Minor Trivial
2 1 4 0 0 0 1 2 4 2 0
Major Major Major Minor
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% Of Agent-Specific Cases (95% CI) 0.7 0.3 1.5 0 0 0 33 22.2 10 5
(0.21–2.8) (0.07–2.1) (0.6–3.9) (0–43) (0–56) (0–66) (6.1–79) (6–55) (4–23) (1.4–16.5) 0
we found the risk of bleeding was greater with the novel anticoagulants than the antiplatelets. Because of obvious inability to randomize patients, it is possible the patients ingesting antiplatelet agents had different baseline characteristics than those ingesting novel anticoagulants. The data collected are limited by the retrospective nature of the study and rely on the completeness and accuracy of the poison control center record. Although all poison control centers use a standard process and criteria for data entry,21 the limitation nonetheless exists. In this study, we opted to focus on select individual poison centers rather than the aggregate data from the American Association of Poison Control Centers. Doing so permitted us full access to the free-text data, which enabled abstractors to have more individual case detail and improve the quality of the data abstracted. Because the variables were limited mostly to dichotomous variables (eg, bleeding or no bleeding), some of the inherent limitations of a retrospective study were likely minimized.22 Furthermore, the study is limited by the short duration of follow-up because it is possible some patients developed bleeding complications after the last follow-up. Although we believe this is unlikely because the majority of contact with the poison control center was by a health care professional, one would assume the poison control center would be recontacted if hemorrhage did occur. Last, we were not able to determine whether some of these cases involved acute ingestions compared with acute-on-chronic ingestions. Intuitively, one might assume the risk of bleeding would be greater in an acute-on-chronic ingestion than in an isolated acute ingestion. This decision was made before initiation of the data abstraction; not every case documents the chronicity of every drug ingested, and there was concern for excluding cases with potentially significant outcome simply because of lack of documentation. The majority of cases in this study involved antiplatelet agents, specifically, clopidogrel, rather than the novel anticoagulants. More prescriptions are written annually in the United States for clopidogrel than for any of the other drugs in this study.23 This study encompasses 10 years; the novel anticoagulants were not approved for many of these years. Because so many of these cases involved clopidogrel compared with the novel anticoagulants, the confidence intervals around the novel anticoagulants are much larger than around clopidogrel. Consequently, the exact risk of bleeding with the novel anticoagulants is less clearly defined. DISCUSSION This study examined the risk of bleeding after intentional overdose with novel anticoagulants or antiplatelet agents. The factor Xa inhibitors can work Volume
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Table 3. Cases with hemorrhage. Case
Age, Years
Sex
Drug
Bleeding Location
Bleeding Classification
Treatment*
Outcome
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
57 58 52 60 61 50 46 18 34 76 59 49 63 63 69 42
M M M M M M M F M F F M F F F M
Apixaban Clopidogrel Clopidogrel Clopidogrel Clopidogrel Clopidogrel Clopidogrel Clopidogrel Dabigatran Dabigatran Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban
Unknown Oozing from wrist laceration Epistaxis Subarachnoid GI Bleed IV line oozing Oozing from wrist laceration Vaginal bleeding GI bleed GI bleed Gingival Intracranial hemorrhage GI bleed GI bleed GI bleed GI bleed
Major Minor Trivial Major Major Trivial Trivial Trivial Major Major Minor Major Major Major Major Minor
Unknown FFP None None (hemodialysis for lithium) DDAVP, PRBC None None None Hemodialysis Vitamin K, FFP Vitamin K, FFP DDAVP, FFP PCC, PRBC PCC FFP, PRBC 3 day observation
Died Survived Survived Survived Survived Survived Survived Survived Survived Died Survived Survived Survived Survived Survived Survived
M, male; FFP, fresh frozen plasma; GI, gastrointestinal; DDAVP, desmopressin; PRBC, packed RBCs; IV, intravenous; F, female; PCC, pooled complex concentrate. *Denotes treatment aimed at reversal of drug or control of bleeding. Does not denote all treatment.
directly or indirectly. The oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban bind to the active site on Xa and inhibit both free and clot-associated factor Xa. In contrast, indirect Xa inhibitors (eg, fondaparinux) bind to antithrombin III. The subsequent conformational change results in inhibition of factor Xa.24 The antiplatelet agents (ticagrelor, clopidogrel, prasugrel, and ticagrelor) block platelet activation. The P2Y12 receptor is normally activated by adenosine diphosphate, thereby inducing signal transduction and platelet activation.25 These drugs inhibit the adenosine diphosphate receptor, ultimately preventing platelet activation. Previous investigations have concluded hemorrhage is unlikely to occur after pediatric exploratory ingestions of these agents. However, other poison control centers have reported bleeding involving these agents. The clinical characteristics of cases involving factor Xa inhibitors at 8 regional poison control centers in 9 states have previously been reported.18 In that series of 223 patients, all cases of bleeding involved long-term ingestions; no cases of hemorrhage after acute overdose were reported. One reason for the discrepancy between the current study and that study is that the previous study included only 12 cases (6%) involving suicide attempts. Similarly, a separate study examined all cases of dabigatran and rivaroxaban reported to a poison control center.17 Of the 56 cases identified, only 4 cases of dabigatran and 1 case of rivaroxaban involved an acute overdose. Thus, similar to the first study, the majority of the cases involved patients receiving therapeutic dosing. Literature involving acute overdoses with the novel anticoagulants or antiplatelet agents is primarily limited to Volume
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case reports. In the single case of acute clopidogrel overdose reported, a 49-year-old man ingested 1,650 mg of clopidogrel.16 No hemorrhagic complications were noted. Similarly, among the novel anticoagulants, several case reports involving acute overdose described patients with either no hemorrhage or hemorrhage that would be classified as trivial or minor.5-6,8-10,12,14,15 Conversely, a case of a 85-year-old man with an intentional ingestion of dabigatran was reported,26 and the bleeding described would be classified as major bleeding by the current study’s definitions. Perhaps even more than most case series, the outcome noted in each of the previously published case reports involving acute overdose is heavily limited by selection bias. Thus, the risk of hemorrhage was unknown before this study. In contrast to pediatric exploratory ingestions of these agents, in which there does not appear to be a risk of hemorrhage,18 it appears that intentional acute overdose is associated with a significant risk of hemorrhage. This difference is likely related to larger quantities of drug ingested with intentional ingestions. The risk of hemorrhage appears greater with novel anticoagulants compared with the antiplatelet antagonists. The risk of hemorrhage after intentional ingestion of novel anticoagulant and antiplatelet medications is not negligible. The risk is greater with the anticoagulants than the antiplatelet agents. Supervising editor: Lewis S. Nelson, MD Author affiliations: From the Department of Emergency Medicine, Division of Medical Toxicology, University of Southern California, Los Angeles, CA (Levine, Spyres); the Department of Emergency Medicine, Division of Medical Toxicology, Carolinas Medical Center, Annals of Emergency Medicine 5
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Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications Charlotte, NC (Beuhler); the Department of Emergency Medicine, Division of Medical Toxicology (Pizon) and the Department of Critical Care Medicine (Skolnik), University of Pittsburgh, Pittsburgh, PA; the California Poison Control System, San Diego Division, San Diego, CA (Cantrel); and the Banner Poison & Drug Information Center, Banner University Medical Center–Phoenix, Phoenix, AZ (LoVecchio, Brooks). Author contributions: ML developed the concept/study design, performed data analysis, and assisted with manuscript preparation. MCB, AP, FLC, and ABS assisted with data abstraction and manuscript preparation. DEB and MBS helped develop the concept/study design, and assisted with manuscript preparation. FL performed the statistical analysis and assisted with manuscript preparation. ML takes responsibility for the paper as a whole. All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. Publication dates: Received for publication February 17, 2017. Revisions received June 4, 2017, and August 5, 2017. Accepted for publication August 16, 2017.
REFERENCES 1. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with two doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. 2011;123:2363-2372. 2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: 1139-1151. 3. Levine M, Goldstein JH. Bleeding complications of targeted oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2014;1:504-509. 4. Levine M, Pizon AF, Padilla-Jones A, et al. Warfarin overdose: a 25 year experience. J Med Toxicol. 2014;10:156-164. 5. Pfeiffer H, Herbst L, Schwarze B, et al. Massive intoxication with rivaroxaban, phenprocoumon, and diclofenac: a case report. Medicine (Baltimore). 2016;95:e5343.
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6. Repplinger DJ, Hoffman RS, Nelson LS, et al. Lack of significant bleeding despite large acute rivaroxaban overdose confirmed with whole blood concentrations. Clin Toxicol. 2016;54:647-649. 7. Lehmann T, Hofer KE, Baumann M, et al. Massive human rivaroxaban overdose. Thromb Haemost. 2014;112:834-836. 8. Sajkov D, Gallus A. Accidental rivaroxaban overdose in a patient with pulmonary embolism: some lessons for managing new oral anticoagulants. Clin Med Insights Case Rep. 2015;8:57-59. 9. Barton J, Wong A, Graudins A. Anti-X activity in apixaban overdose: a case report. Clin Toxicol (Phila). 2016;54:871-873. 10. Peetermans M, Pollack C Jr, Reilly P, et al. Idarucizumab for dabigatran overdose. Clin Toxicol (Phila). 2016;54:644-646. 11. Shapiro S, Bhatnagar N, Khan A, et al. Idarucizumab for dabigatran overdose in a child. Br J Haematol. 2016; http://dx.doi.org/10.1111/ bjh.14371. 12. Vlad I, Armstrong J, Ridgley J, et al. Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. Clin Toxicol (Phila). 2016;54:286-289. 13. Mumoli N, Cei M, Fiorini M, et al. Conservative management of intentional massive dabigatran overdose. Blood Coagul Fibrinolysis. 2015;26:225-229. 14. Chiew AL, Khamoudes D, Chan BS, et al. Use of continuous venovenous haemodiafiltration therapy in dabigatran overdose. Clin Toxicol (Phila). 2014;52:283-287. 15. Woo JS, Kapadia N, Phanco SE, et al. Positive outcome after intentional overdose of dabigatran. J Med Toxicol. 2013;9:192-195. 16. Kocabay G, Okcular I, Akkaya V, et al. Suicide attempt with clopidogrel. Hum Exp Toxicol. 2006;25:731-734. 17. Stevenson JW, Minns AB, Smollin C, et al. An observational case series of dabigatran and rivaroxaban exposures reported to a poison control system. Am J Emerg Med. 2014;32:1077-1184. 18. Spiller HA, Mowry JB, Aleguas A, et al. An observational study of the factor Xa inhibitors rivaroxaban and apixaban as reported to eight poison centers. Ann Emerg Med. 2016;67:189-195. 19. Conway SE, Schaeffer SE, Harrison DL. Evaluation of dabigatran exposures reported to poison control centers. Ann Pharmacother. 2014;48:354-360. 20. Levine M, Ruha AM, Padilla-Jones A, et al. Bleeding following rattlesnake envenomation in patients with preenvenomation use of antiplatelet or anticoagulant medications. Acad Emerg Med. 2014;21:301-307. 21. AAPCC Board of Directors. National Poison Data System (NPDS): NPDS Coding Users’ Manual, Version 3.2. Orange, CA: American Association of Poison Control Centers; 2016. 22. Gilbert EH, Lowenstein SR, Koziol-McLain J, et al. Chart reviews in emergency medicine research: what are the methods? Ann Emerg Med. 1996;27:305-308. 23. Lowest Med. The top 50 prescription drugs filled in the US. Available at: https://www.lowestmed.com/top-50-prescription-drugs-filled/. Accessed April 20, 2017. 24. Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015;16:11-17. 25. Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest. 2004;113:340-345. 26. Montaruli B, Erroi L, Vitale C, et al. Dabigatran overdose: case report of laboratory coagulation parameters and hemodialysis of an 85-year old man. Blood Coagul Fibrinolysis. 2015;26:225-229.
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Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications Michael Levine, MD*; Michael C. Beuhler, MD; Anthony Pizon, MD; F. Lee Cantrel, PharmD; Meghan B. Spyres, MD; Frank LoVecchio, DO; Aaron B. Skolnik, MD; Daniel E. Brooks, MD *Corresponding Author. E-mail: [email protected].
Study objective: In recent years, the use of novel anticoagulants and antiplatelet agents has become widespread. Little is known about the toxicity and bleeding risk of these agents after acute overdose. The primary objective of this study is to evaluate the relative risk of all bleeding and major bleeding in patients with acute overdose of novel antiplatelet and anticoagulant medications. Methods: This study is a retrospective study of acute ingestion of apixaban, clopidogrel, ticlopidine, dabigatran, edoxaban, prasugrel, rivaroxaban, and ticagrelor reported to 7 poison control centers in 4 states during a 10-year span. The prevalence of bleeding for each agent was calculated, and hemorrhage was classified as trivial, minor, or major. Results: A total of 322 acute overdoses were identified, with the majority of cases involving clopidogrel (260; 80.7%). Hemorrhage occurred in 16 cases (4.9%), including 7 cases of clopidogrel, 6 cases of rivaroxaban, 2 cases of dabigatran, and 1 case of apixaban. Most cases of hemorrhage were classified as major (n¼9). Comparing the novel anticoagulants with the P2Y12 receptor inhibitors, the relative risk for any bleeding with novel anticoagulant was 6.68 (95% confidence interval 2.63 to 17.1); the relative risk of major bleeding was 18.1 (95% confidence interval 3.85 to 85.0). Conclusion: Acute overdose of novel anticoagulants or antiplatelet agents is associated with a small risk of significant hemorrhage. The risk is greater with the factor Xa inhibitors and direct thrombin inhibitors than with the P2Y12 receptor antagonists. [Ann Emerg Med. 2017;-:1-6.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2017 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2017.08.046
INTRODUCTION Antiplatelet and anticoagulant therapy has undergone a revolutionary change in the past decade. The advent of adenosine diphosphate receptor antagonists and the novel anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) has expanded the options available for prevention and treatment of thromboemboli. At therapeutic dosing, the primary toxicity of the antiplatelet and anticoagulant agents is hemorrhage. This risk may be dose dependent and is increased in patients with advanced age.1,2 However, the risk of bleeding appears to be similar with the direct thrombin inhibitors compared with the factor Xa inhibitors.3 Although it is known from studies on warfarin that patients with acute overdose may develop hemorrhagic complications,4 it is unknown at what rate hemorrhagic complications occur after an acute overdose of the novel anticoagulants or antiplatelet agents. Most of the current literature involving acute overdoses with these agents is limited to case reports.5-16 The majority Volume
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of these describe only minimal or no bleeding. There are also 3 poison control center studies that have been performed.1719 One series reported all calls involving dabigatran and rivaroxaban,17 a separate study examined all calls involving rivaroxaban and apixaban,18 and a third study examined dabigatran ingestions.19 However, these 3 poison control center–based studies were heterogeneous and included all calls involving these agents, not just intentional overdoses. It was hypothesized that the risk of bleeding was greater for the novel anticoagulants compared with nonsalicylatebased antiplatelet agents. Thus, the primary purpose of this study was to evaluate the bleeding risk in patients with acute or acute-on-chronic intentional overdoses with these agents, and to compare the risk of bleeding between the novel anticoagulants with the antiplatelet agents. MATERIALS AND METHODS This retrospective study of poison control center calls involving patients with intentional ingestions of novel Annals of Emergency Medicine 1
Levine et al
Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications
Editor’s Capsule Summary
What is already known on this topic Patients with intentional overdose of antiplatelet and novel anticoagulant medications have an increased risk of hemorrhagic complications. The bleeding risk from various classes of anticoagulant medications is not well characterized. What question this study addressed What is the risk of bleeding after intentional overdose with antiplatelet and novel anticoagulant medications? What this study adds to our knowledge Authors identified 322 cases of intentional overdose during 10 years in 7 US poison center databases. The majority of cases (83.9%) involved antiplatelet agents. Bleeding occurred in 16 cases (4.9%) (7 antiplatelet, 9 novel anticoagulant) and was considered major in 9 cases. How this is relevant to clinical practice Bleeding after overdose with antiplatelet and novel anticoagulant medications is uncommon. Novel anticoagulants carry a greater risk.
antiplatelet or anticoagulant medications was approved by the institutional review board at each of the participating centers. Such cases can include acute and acute-on-chronic ingestions. The data were pooled from 7 poison control centers in 4 states. The primary outcome measurement was the presence of bleeding during the index call or during the follow-up period. A secondary objective was to classify the type of bleeding, should it occur. Setting and Selection of Participants The deidentified data were pooled from 7 poison control centers covering 4 states. These poison control centers collectively receive 670,000 cases yearly and cover a population of 53 million. At each of these centers, the data are entered into commercially available patient management software that collects the same basic data on all patients. This software at each poison control center was queried for all calls between January 1, 2005, and December 31, 2014, for intentional exposures involving the following medications: apixaban, clopidogrel, dabigatran, edoxaban, prasugrel, rivaroxaban, ticagrelor, and ticlopidine. Cases involving drug information without acute exposure, cases involving bleeding while receiving therapeutic dosing, 2 Annals of Emergency Medicine
pediatric (6 years or younger) exploratory ingestions, and accidental double-dose ingestions were excluded. Multiple ingestants were permitted but cases involving warfarin or rodenticides were excluded. Thus, the final data set involved subjects older than 6 years and with intentional ingestions. Data Collection and Processing and Primary Data Analysis Data were collected on predesigned data abstraction sheets and entered into Excel 2010 (version 14.0.7184.5000 Microsoft, Redmond, WA). Data abstraction was performed by a single abstractor at each site. Ten percent of charts were randomly selected by each center, a separate investigator not involved with the original abstraction abstracted those records, and a k statistic was calculated to assess interrater reliability. The individuals performing the data abstraction were aware of the study but not the specific hypothesis being tested. The data abstracted included the implicated agent, demographic information (eg, age, sex), treatment rendered, duration of follow-up, and outcome. The narrative sections of each chart were reviewed to augment data abstraction. If bleeding did occur, the type of bleeding and subsequent interventions were also recorded. Data from each of the centers were pooled. The proportions of bleeding for each agent were calculated, and associated 95% confidence intervals were determined with the Wilson procedure. A 2-tailed analysis was performed. The relative risk of bleeding for novel anticoagulants compared with antiplatelet agents was calculated. All statistical analysis was performed with Stata 2007 (StataCorp, College Station, TX). A k statistic was calculated to assess interrater reliability. Bleeding was classified as major, minor, or trivial, according to previous toxicology literature.20 Major bleeding was defined as fatal bleeding, bleeding associated with hemodynamic instability, bleeding requiring an invasive therapeutic intervention (eg, endoscopy), bleeding requiring the transfusion of one or more units of packed RBCs, or bleeding into an enclosed space (eg, retroperitoneal, intracranial). Minor bleeding was defined as any bleeding resulting in an admission or prolonged observation, but not requiring the administration of packed RBCs or the performance of any invasive procedures. Transfusion of fresh frozen plasma to treat a coagulopathy in the setting of bleeding, without the need to transfuse RBCs, was considered minor bleeding. Trivial bleeding was defined as bleeding not requiring any intervention or prolonged observation, and included persistent oozing from puncture wounds and self-limited bleeding not requiring intervention (eg, epistaxis, hemorrhoidal bleeding). Volume
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Suturing of self-inflicted laceration without any other intervention was considered trivial. Calls were classified as originating from home or from a hospital. Calls from emergency medical services were classified as originating from home. Successful follow-up was defined as at least one communication with the poison control center at least 4 hours after the index call. RESULTS During the study period, a total of 322 cases were identified (Figure). The median age was 50 years (interquartile range 41 to 59). Men accounted for 207 cases (64.3%). The majority of cases (260; 80.7%) involved clopidogrel. There were 40 cases (12.4%) of rivaroxaban, 9 (2.8%) of dabigatran, 5 (1.6%) of prasugrel, 3 (0.93%) of ticagrelor, and 2 (0.62%) of ticlopidine ingestion that were identified (Table 1). Collectively, antiplatelet agents
accounted for 270 cases (83.9%), whereas the novel anticoagulants accounted for 52 (16%). The k statistic was greater than 0.9 for each variable abstracted. Other statistics were performed as outlined in the “Materials and Methods” section. Overall, bleeding developed in 16 (4.9%) cases, including 7 cases of clopidogrel, 6 cases of rivaroxaban, 2 cases of dabigatran, and 1 case of apixaban. Bleeding was classified as major in 9 cases, minor in 3, and trivial in 4. No cases of hemorrhage were identified with prasugrel, ticagrelor, ticlopidine, or edoxaban. The classification of hemorrhage is presented in Table 2. Details of these 16 patients are presented in Table 3. After overdose, patients ingesting the novel anticoagulants are more likely than those ingesting the antiplatelet agents to develop any bleeding (relative risk 6.68; 95% confidence interval 2.63 to 17.1) and major bleeding (relative risk 18.1; 95% confidence interval 3.85 to 85.0).
1958 total cases idenfied by search
638 cases idenfied and excluded
1320 total remained eligible
990 cases idenfied as accidental double dose or complicaon of therapeuc use
330 Acute adult ingesons
8 with concurrent warfarin or rodencide
322 cases
Figure. Screening population with subsequent exclusion. Volume
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Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications Table 1. Cases by class and agent. Class
Agent
Antiplatelet P2Y12 inhibitors
Number of Cases (% of Total)
Clopidogrel Prasugrel Ticagrelor Ticlopidine
Anticoagulant Direct thrombin inhibitors Factor Xa inhibitors
260 5 3 2
Dabigatran Rivaroxaban Apixaban Edoxaban
(80.7) (1.6) (0.93) (0.62)
9 (2.8) 40 (12.4) 3 (0.93) 0
LIMITATIONS This study has several limitations. There is no mandatory reporting to poison control centers and calls are often initiated by providers only peripherally involved in the patients’ care. Thus, incomplete or inaccurate information may be provided. In addition, there is a possibility of a selection bias in which only the sickest patients are reported to a poison control center; this would bias the estimated incidence to be higher than expected. Ingestions including multiple substances were included, which could affect the conclusions about attributing the bleeding to the novel antiplatelet and or anticoagulant medications; however, effort was made to exclude other ingestants that are known to cause bleeding. Also, serum confirmation of the ingestion was not performed for these patients, making it impossible to say with certainty that ingestion occurred, only that these are cases of reported ingestion. In this study, follow-up was defined as a call after 4 hours. We assumed a repeated telephone call would be generated to the poison control center. It is possible patients developed bleeding after the last telephone call and the case was not reported. If this happened, the risk of bleeding would be even larger than reported. In this study, Table 2. Incidence of hemorrhage and classification.
Class
Agent
Antiplatelet
Clopidogrel
Anticoagulant
Prasugrel Ticagrelor Ticlopidine Apixaban Dabigatran Rivaroxaban Edoxaban
Classification of Hemorrhage
No. of Cases
Major Minor Trivial
2 1 4 0 0 0 1 2 4 2 0
Major Major Major Minor
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% Of Agent-Specific Cases (95% CI) 0.7 0.3 1.5 0 0 0 33 22.2 10 5
(0.21–2.8) (0.07–2.1) (0.6–3.9) (0–43) (0–56) (0–66) (6.1–79) (6–55) (4–23) (1.4–16.5) 0
we found the risk of bleeding was greater with the novel anticoagulants than the antiplatelets. Because of obvious inability to randomize patients, it is possible the patients ingesting antiplatelet agents had different baseline characteristics than those ingesting novel anticoagulants. The data collected are limited by the retrospective nature of the study and rely on the completeness and accuracy of the poison control center record. Although all poison control centers use a standard process and criteria for data entry,21 the limitation nonetheless exists. In this study, we opted to focus on select individual poison centers rather than the aggregate data from the American Association of Poison Control Centers. Doing so permitted us full access to the free-text data, which enabled abstractors to have more individual case detail and improve the quality of the data abstracted. Because the variables were limited mostly to dichotomous variables (eg, bleeding or no bleeding), some of the inherent limitations of a retrospective study were likely minimized.22 Furthermore, the study is limited by the short duration of follow-up because it is possible some patients developed bleeding complications after the last follow-up. Although we believe this is unlikely because the majority of contact with the poison control center was by a health care professional, one would assume the poison control center would be recontacted if hemorrhage did occur. Last, we were not able to determine whether some of these cases involved acute ingestions compared with acute-on-chronic ingestions. Intuitively, one might assume the risk of bleeding would be greater in an acute-on-chronic ingestion than in an isolated acute ingestion. This decision was made before initiation of the data abstraction; not every case documents the chronicity of every drug ingested, and there was concern for excluding cases with potentially significant outcome simply because of lack of documentation. The majority of cases in this study involved antiplatelet agents, specifically, clopidogrel, rather than the novel anticoagulants. More prescriptions are written annually in the United States for clopidogrel than for any of the other drugs in this study.23 This study encompasses 10 years; the novel anticoagulants were not approved for many of these years. Because so many of these cases involved clopidogrel compared with the novel anticoagulants, the confidence intervals around the novel anticoagulants are much larger than around clopidogrel. Consequently, the exact risk of bleeding with the novel anticoagulants is less clearly defined. DISCUSSION This study examined the risk of bleeding after intentional overdose with novel anticoagulants or antiplatelet agents. The factor Xa inhibitors can work Volume
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Table 3. Cases with hemorrhage. Case
Age, Years
Sex
Drug
Bleeding Location
Bleeding Classification
Treatment*
Outcome
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
57 58 52 60 61 50 46 18 34 76 59 49 63 63 69 42
M M M M M M M F M F F M F F F M
Apixaban Clopidogrel Clopidogrel Clopidogrel Clopidogrel Clopidogrel Clopidogrel Clopidogrel Dabigatran Dabigatran Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban
Unknown Oozing from wrist laceration Epistaxis Subarachnoid GI Bleed IV line oozing Oozing from wrist laceration Vaginal bleeding GI bleed GI bleed Gingival Intracranial hemorrhage GI bleed GI bleed GI bleed GI bleed
Major Minor Trivial Major Major Trivial Trivial Trivial Major Major Minor Major Major Major Major Minor
Unknown FFP None None (hemodialysis for lithium) DDAVP, PRBC None None None Hemodialysis Vitamin K, FFP Vitamin K, FFP DDAVP, FFP PCC, PRBC PCC FFP, PRBC 3 day observation
Died Survived Survived Survived Survived Survived Survived Survived Survived Died Survived Survived Survived Survived Survived Survived
M, male; FFP, fresh frozen plasma; GI, gastrointestinal; DDAVP, desmopressin; PRBC, packed RBCs; IV, intravenous; F, female; PCC, pooled complex concentrate. *Denotes treatment aimed at reversal of drug or control of bleeding. Does not denote all treatment.
directly or indirectly. The oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban bind to the active site on Xa and inhibit both free and clot-associated factor Xa. In contrast, indirect Xa inhibitors (eg, fondaparinux) bind to antithrombin III. The subsequent conformational change results in inhibition of factor Xa.24 The antiplatelet agents (ticagrelor, clopidogrel, prasugrel, and ticagrelor) block platelet activation. The P2Y12 receptor is normally activated by adenosine diphosphate, thereby inducing signal transduction and platelet activation.25 These drugs inhibit the adenosine diphosphate receptor, ultimately preventing platelet activation. Previous investigations have concluded hemorrhage is unlikely to occur after pediatric exploratory ingestions of these agents. However, other poison control centers have reported bleeding involving these agents. The clinical characteristics of cases involving factor Xa inhibitors at 8 regional poison control centers in 9 states have previously been reported.18 In that series of 223 patients, all cases of bleeding involved long-term ingestions; no cases of hemorrhage after acute overdose were reported. One reason for the discrepancy between the current study and that study is that the previous study included only 12 cases (6%) involving suicide attempts. Similarly, a separate study examined all cases of dabigatran and rivaroxaban reported to a poison control center.17 Of the 56 cases identified, only 4 cases of dabigatran and 1 case of rivaroxaban involved an acute overdose. Thus, similar to the first study, the majority of the cases involved patients receiving therapeutic dosing. Literature involving acute overdoses with the novel anticoagulants or antiplatelet agents is primarily limited to Volume
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case reports. In the single case of acute clopidogrel overdose reported, a 49-year-old man ingested 1,650 mg of clopidogrel.16 No hemorrhagic complications were noted. Similarly, among the novel anticoagulants, several case reports involving acute overdose described patients with either no hemorrhage or hemorrhage that would be classified as trivial or minor.5-6,8-10,12,14,15 Conversely, a case of a 85-year-old man with an intentional ingestion of dabigatran was reported,26 and the bleeding described would be classified as major bleeding by the current study’s definitions. Perhaps even more than most case series, the outcome noted in each of the previously published case reports involving acute overdose is heavily limited by selection bias. Thus, the risk of hemorrhage was unknown before this study. In contrast to pediatric exploratory ingestions of these agents, in which there does not appear to be a risk of hemorrhage,18 it appears that intentional acute overdose is associated with a significant risk of hemorrhage. This difference is likely related to larger quantities of drug ingested with intentional ingestions. The risk of hemorrhage appears greater with novel anticoagulants compared with the antiplatelet antagonists. The risk of hemorrhage after intentional ingestion of novel anticoagulant and antiplatelet medications is not negligible. The risk is greater with the anticoagulants than the antiplatelet agents. Supervising editor: Lewis S. Nelson, MD Author affiliations: From the Department of Emergency Medicine, Division of Medical Toxicology, University of Southern California, Los Angeles, CA (Levine, Spyres); the Department of Emergency Medicine, Division of Medical Toxicology, Carolinas Medical Center, Annals of Emergency Medicine 5
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Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications Charlotte, NC (Beuhler); the Department of Emergency Medicine, Division of Medical Toxicology (Pizon) and the Department of Critical Care Medicine (Skolnik), University of Pittsburgh, Pittsburgh, PA; the California Poison Control System, San Diego Division, San Diego, CA (Cantrel); and the Banner Poison & Drug Information Center, Banner University Medical Center–Phoenix, Phoenix, AZ (LoVecchio, Brooks). Author contributions: ML developed the concept/study design, performed data analysis, and assisted with manuscript preparation. MCB, AP, FLC, and ABS assisted with data abstraction and manuscript preparation. DEB and MBS helped develop the concept/study design, and assisted with manuscript preparation. FL performed the statistical analysis and assisted with manuscript preparation. ML takes responsibility for the paper as a whole. All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. Publication dates: Received for publication February 17, 2017. Revisions received June 4, 2017, and August 5, 2017. Accepted for publication August 16, 2017.
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6. Repplinger DJ, Hoffman RS, Nelson LS, et al. Lack of significant bleeding despite large acute rivaroxaban overdose confirmed with whole blood concentrations. Clin Toxicol. 2016;54:647-649. 7. Lehmann T, Hofer KE, Baumann M, et al. Massive human rivaroxaban overdose. Thromb Haemost. 2014;112:834-836. 8. Sajkov D, Gallus A. Accidental rivaroxaban overdose in a patient with pulmonary embolism: some lessons for managing new oral anticoagulants. Clin Med Insights Case Rep. 2015;8:57-59. 9. Barton J, Wong A, Graudins A. Anti-X activity in apixaban overdose: a case report. Clin Toxicol (Phila). 2016;54:871-873. 10. Peetermans M, Pollack C Jr, Reilly P, et al. Idarucizumab for dabigatran overdose. Clin Toxicol (Phila). 2016;54:644-646. 11. Shapiro S, Bhatnagar N, Khan A, et al. Idarucizumab for dabigatran overdose in a child. Br J Haematol. 2016; http://dx.doi.org/10.1111/ bjh.14371. 12. Vlad I, Armstrong J, Ridgley J, et al. Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. Clin Toxicol (Phila). 2016;54:286-289. 13. Mumoli N, Cei M, Fiorini M, et al. Conservative management of intentional massive dabigatran overdose. Blood Coagul Fibrinolysis. 2015;26:225-229. 14. Chiew AL, Khamoudes D, Chan BS, et al. Use of continuous venovenous haemodiafiltration therapy in dabigatran overdose. Clin Toxicol (Phila). 2014;52:283-287. 15. Woo JS, Kapadia N, Phanco SE, et al. Positive outcome after intentional overdose of dabigatran. J Med Toxicol. 2013;9:192-195. 16. Kocabay G, Okcular I, Akkaya V, et al. Suicide attempt with clopidogrel. Hum Exp Toxicol. 2006;25:731-734. 17. Stevenson JW, Minns AB, Smollin C, et al. An observational case series of dabigatran and rivaroxaban exposures reported to a poison control system. Am J Emerg Med. 2014;32:1077-1184. 18. Spiller HA, Mowry JB, Aleguas A, et al. An observational study of the factor Xa inhibitors rivaroxaban and apixaban as reported to eight poison centers. Ann Emerg Med. 2016;67:189-195. 19. Conway SE, Schaeffer SE, Harrison DL. Evaluation of dabigatran exposures reported to poison control centers. Ann Pharmacother. 2014;48:354-360. 20. Levine M, Ruha AM, Padilla-Jones A, et al. Bleeding following rattlesnake envenomation in patients with preenvenomation use of antiplatelet or anticoagulant medications. Acad Emerg Med. 2014;21:301-307. 21. AAPCC Board of Directors. National Poison Data System (NPDS): NPDS Coding Users’ Manual, Version 3.2. Orange, CA: American Association of Poison Control Centers; 2016. 22. Gilbert EH, Lowenstein SR, Koziol-McLain J, et al. Chart reviews in emergency medicine research: what are the methods? Ann Emerg Med. 1996;27:305-308. 23. Lowest Med. The top 50 prescription drugs filled in the US. Available at: https://www.lowestmed.com/top-50-prescription-drugs-filled/. Accessed April 20, 2017. 24. Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015;16:11-17. 25. Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest. 2004;113:340-345. 26. Montaruli B, Erroi L, Vitale C, et al. Dabigatran overdose: case report of laboratory coagulation parameters and hemodialysis of an 85-year old man. Blood Coagul Fibrinolysis. 2015;26:225-229.
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