An Observational Case Series of Dabigatran and Rivaroxaban Exposures Reported to a Poison Control System John W. Stevenson MS, Alicia B. Minns MD, Craig Smollin MD, Timothy E. Albertson MD, PhD, F. Lee Cantrell PharmD, Christian Tomaszewski MD, MS, Richard F. Clark MD PII: DOI: Reference:

S0735-6757(14)00275-7 doi: 10.1016/j.ajem.2014.04.031 YAJEM 54261

To appear in:

American Journal of Emergency Medicine

Received date: Revised date: Accepted date:

16 February 2014 23 March 2014 15 April 2014

Please cite this article as: Stevenson John W., Minns Alicia B., Smollin Craig, Albertson Timothy E., Cantrell F. Lee, Tomaszewski Christian, Clark Richard F., An Observational Case Series of Dabigatran and Rivaroxaban Exposures Reported to a Poison Control System, American Journal of Emergency Medicine (2014), doi: 10.1016/j.ajem.2014.04.031

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ACCEPTED MANUSCRIPT An Observational Case Series of Dabigatran and Rivaroxaban Exposures Reported to a Poison Control System

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John W. Stevenson, MS+ Alicia B. Minns, MD*~ Craig Smollin, MD~ Timothy E. Albertson, MD, PhD #, ~ F. Lee Cantrell, PharmD*~ Christian Tomaszewski, MD, MS*~ Richard F. Clark, MD*~

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Address for correspondence: Richard F. Clark, MD 200 W. Arbor Dr. San Diego, CA 92103-8676 [email protected]

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From: *UCSD Division of Medical Toxicology, Department of Emergency Medicine ~California Poison Control System +UCSD School of Medicine # UC Davis School of Medicine, Departments of Internal Medicine and Emergency Medicine

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Key words: dabigatran, rivaroxaban, poisoning, treatment

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Conflict of interest: None of the authors have any known conflict of interest to report.

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JS, AM and RC conceived the study, designed the methods, and obtained IRB approval. RC, AM, JS, CS, LC and TA supervised the conduct of the trial and data collection. JS and RC drafted the manuscript, and all authors contributed substantially to its revision. RC and JS takes responsibility for the paper as a whole. Word count: 4000

ACCEPTED MANUSCRIPT Abstract

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Objective: Characterize clinical presentations and outcomes of dabigatran and rivaroxaban exposures reported to a poison control system.

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Methods: Data for cases of dabigatran and rivaroxaban exposures called into the California Poison Control System from January 2011 through July 2013 were collected. Data collected included patient demographics, type of exposure, medication, dosage, vital signs, laboratory values, interventions, outcomes, and disposition. Exclusion criteria included confirmed nonexposures or miscoded cases.

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Results: A total of 56 cases were identified, with 7 excluded, leaving 37 dabigatran and 12 rivaroxaban cases. Children age 12 or less accounted for 5 dabigatran and 2 rivaroxaban cases. Bleeding was reported in 15 dabigatran cases. There were 4 cases of acute self-harm overdose with dabigatran ranging from 1800-3900 mg. Mild bleeding was reported in only one of these overdose cases. There were 2 fatal hemorrhages in dabigatran cases, both in chronic therapeutic dosing. Bleeding was reported in 5 rivaroxaban cases, all in patients with chronic exposure; no deaths were reported. There were no adverse outcomes in pediatric patients. Coagulation parameters did not correlate well with bleeding.

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Conclusions: In our series, the greatest risk of adverse events was in patients chronically taking these agents, irrespective of excess dosing. Acute self-harm ingestions and accidental pediatric ingestions had few adverse effects, although massive overdose can lead to abnormal coagulation studies. It does not appear that single low dose ingestions of either medication will lead to clinically significant bleeding. It may be possible to manage some pediatric exposures and most accidental ingestions with observation.

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Introduction

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Dabigatran etexilate (Pradaxa®) and rivaroxaban (Xarelto®) are new oral anticoagulants approved by the Food and Drug Administration (FDA) in 2010 and 2011 respectively (1, 2). Dabigatran competitively inhibits free and clot-bound thrombin by binding to thrombin’s active site (1, 3). Rivaroxaban inhibits free, prothombinase-complex-bound, and clot-bound factor Xa by binding to the active site (2, 3). Table 1 summarizes pharmacokinetic and pharmacodynamic information on these agents.

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Methods

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Advantages of these new anticoagulants over warfarin include more predictable pharmacokinetic profiles, far fewer drug and food interactions and no need to regularly monitor coagulation studies such as prothrombin time (PT) or partial thromboplastin time (PTT). Disadvantages include a lack of clinical experience with these medications and a lack of specific reversal agents. Concerns have been raised about post FDA approval rates of bleeding induced by these medications, trauma associated bleeding in patients on these medications, and how these medications would perform in the elderly and renally impaired (4-7). There is also concern over the management of large overdoses and the potential challenges associated with pediatric ingestions. Various types of bleeding associated with these agents have been reported including cerebral hemorrhage, hemopericardium, rectal bleeding, hematuria, and diffuse ecchymosis (8-12), but a larger number of cases are needed to assess potential toxicity. The purpose of this study was to further characterize the clinical presentation and outcomes of dabigatran and rivaroxaban overdoses and toxicity as an observational case series.

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This study combined a retrospective review and prospective observational case series. Approval from our institutional review board was granted for the design and methods. The California Poison Control System (CPCS) is composed of four regional sites. It serves approximately 38 million people, and in 2012 received approximately 300,000 calls. Each case is entered into a shared database (WBM Software- Visual Dotlab Enterprise, Fresno, CA). Data for cases of dabigatran and rivaroxaban exposures called into the CPCS from January 1, 2011 through July 30, 2013 were used for analysis. Cases from June 1, 2012 to July 30, 2013 were prospectively collected by telephone and followed after a patient or healthcare practitioner made initial contact with the system. Additionally, the database was retrospectively queried for all previous cases involving these agents from January 1, 2011 to May 31, 2012. Inclusion criteria were cases of exposure to these medications reported to our system. Exclusion criteria included confirmed non-exposures or miscoded cases. Multiple agent exposures involving dabigatran or rivaroxaban were included. In no cases was warfarin or any antiplatelet agent reported as a coingestant. Data for each case were collected by poison information specialists and medical toxicologists on staff. Data collected included: case number, age, gender, vital signs, intent, offending agent(s), medication(s), dosage, laboratory values, interventions, and outcomes. “Outcomes” were

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categorized as either: 1) unable to follow-potentially toxic exposure; 2) no effect-asymptomatic; 3) minimal clinical effects possible; 4) minor effect; 5) moderate effect; 6) major effect; or 7) death. Disposition including hospital admission was categorized as either: 1) admitted to noncritical care unit; 2) admitted to critical care unit; 3) treated evaluated and released from ED; 4) patient lost to follow up/left against medical advice; or 5) other. The nature of the exposure was categorized as unintentional/general, unintentional/therapeutic error, adverse reactiondrug, or intentional/suspected suicide. Present CPCS guidelines and recommendations regarding the management of dabigatran and rivaroxaban are summarized in Table 2.

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Each case was de-identified, and data were extracted. Extracted data included case number, date/time of initial call, nature of exposure, caller site, exposure acuity, hospital flow, outcome, agent involved, dose, age, sex, weight, brief history, past medical history, other agents involved, prescription medications involved, treatments, outcomes, vital signs, PT/INR, PTT, thrombin time, blood urea nitrogen, creatinine, hepatic panel, bleeding, and therapeutic interventions. The time at which any of these values was reported to our poison system was recorded. The highest and lowest value for each parameter in each case was noted.

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Treatments used including activated charcoal, observation, intravenous fluids, hematological agents [fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), Factor VII Inhibitor Bypassing Activity (FEIBA), activated-factor VII (aFVII), factor IX (FIX), packed red blood cells (RBC)], hemodialysis, vasopressors, other medications, intubation, and surgical interventions were recorded. The presence of bruising, active bleeding, or other hematological complications were recorded.

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Normal and abnormal laboratory values were based on our institutional definitions (Table 3). The adult population was defined as >12 years old and the pediatric population was defined as 1.2) was reported in 15 cases; 9 reported INR values that were greater than 2.0. Thirteen of the cases with bleeding reported an INR value; 11 had an elevated value.

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Sixteen of the dabigatran cases reported PTT values. The highest value reported was 464.4s. An elevated value (>34.0s) was reported in 15 cases. All eleven cases with bleeding reported an elevated PTT value.

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The thrombin time was reported in one case with the highest value noted at 100.2s, declining to 26.6s after approximately 13 hours. Fourteen dabigatran cases reported a creatinine value with 10 cases having an elevated creatinine at some point during the case. Seven of these (50%) reported bleeding.

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Two cases of death associated with dabigatran exposures were reported. Both were related to adverse reactions associated with chronic therapeutic ingestion of the drug.

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There were 7 cases of dabigatran accidental extra dosing. The excess doses ranged from 75mg to 750mg. None reported bleeding or adverse reactions. There were 5 cases related to therapeutic error in which the patient mistakenly ingested or was given another individual’s medication. The dose of dabigatran ranged from 75mg to 150mg in this group. Four of these cases involved co-ingestion. None of these cases reported bleeding or adverse reaction.

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There were 4 cases of intentional ingestion of dabigatran in a self-harm gesture (cases 12, 13, 15, and 21) with doses ranging from 1800 to 3900mg. One dose was unknown. Three cases reported peak INR and PTT values that were elevated. Only one of these patients experienced bleeding (see Selected Cases below). One patient refused treatment and left against medical advice. She was lost to follow up. The other 3 were admitted for treatment, received a variety of therapies, and had generally good outcomes. Rivaroxaban Cases Demographics and outcomes of rivaroxaban cases are summarized in Table 7. Bleeding was reported in 5 of 12 (41.7%) cases of rivaroxaban exposure. One case of lower gastrointestinal bleed was associated with diverticulosis, and a case of hematuria was associated with a urinary tract infection. The remaining 3 cases had no identifiable precipitating cause. All 5 these cases were due to adverse reaction related to chronic therapeutic ingestions of the drug. INR values were reported in 7 rivaroxaban cases. All of these cases had an elevated value at some point (>1.2), with the highest value of 15. See Selected Cases and Table 6 for more detail.

ACCEPTED MANUSCRIPT The 5 cases with bleeding reported an elevated peak INR value ranging from 1.4 to 2.6. Only one of these was >2.0.

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PTT values were reported in 5 rivaroxaban cases. All recorded an elevated value at some point. The highest value was 55s. Three cases with bleeding reported a PTT value. The peak values ranged from 35s to 42.3s.

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Only two of the rivaroxaban cases reported a creatinine value, none of which were abnormal. No deaths associated with rivaroxaban toxicity were reported during the duration of this study. There were 4 cases of rivaroxaban extra dose, 3 cases were of a single extra 20mg dose and 1 was of five 20mg doses at once. None of these patients reported any signs of bleeding or adverse reaction. Pediatric Cases

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There were 5 pediatric cases reported involving dabigatran - 2 males and 3 females. The ages ranged from 13 months to 2 years. Four cases involved ingestion of one 150mg dose. The other case was related to therapeutic error (see Selected Cases below). Laboratory values were available for 2 of the pediatric cases. The PTT was elevated in one case, and one was lost to follow up. These cases reported no symptoms, signs of bleeding or adverse reaction.

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Selected Cases

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There were 2 cases of pediatric rivaroxaban ingestion. Both involved 1.5 year old males who ingested their grandparent’s medication. It is unclear how many tablets were potentially ingested. Neither patient presented to a health care facility for evaluation and both were lost to follow up, but no adverse reaction or bleeding was reported.

A 74 year old female prescribed an unknown dose of dabigatran (case #6 in Table 6) was referred to the ED because of laboratory values concerning anemia, acute renal failure and coagulopathy. She presented with hematemesis, melena, and infective colitis. Initial serum creatinine was 5.03. Initial INR and PTT values were elevated beyond the measurable range. The patient was treated with FFP, PCC, multiple units of RBCs, platelets, vitamin K, continuous veno-venous hemofiltration, and multiple vasopressors. On hospital day (HD) 3 her INR, PTT and creatinine values corrected to 3.4, 82.3s and 1.2 respectively; and on HD6 to 1.7, 49.5s, and 0.91 respectively. Despite these interventions, she died on HD7. A 73 year old female (case #11) on dabigatran 150mg twice daily for 6 months fell, striking her head and chest, and developed a hemothorax. Initial INR and PTT were 1.16 and 39.2s respectively. Initial thrombin time was 100.2s. A chest tube was placed, and the patient was treated with hemodialysis and 1 unit of FEIBA. Thrombin time declined to 26.6s approximately

ACCEPTED MANUSCRIPT 13 hours after the initial value. INR and PTT did not change significantly throughout the hospital course. The patient tolerated her treatments well, and returned to stable condition.

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An 85 year old male (case #9) prescribed an unknown dose of dabigatran presented to an ED after a fall and was diagnosed with a subarachnoid hemorrhage. Initial INR and PTT were 2.6 and 66.4s. The patient was treated with FFP, intubation, antibiotics, phenytoin and labetalol. INR and PTT declined to 1.5 and 37.9s on HD6, but despite some initial improvements, the hemorrhage continued to expand. Life support was withdrawn on HD13. The patient died the next day.

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A 34 year old male (case # 12) presented with a suicidal ingestion of 1800mg dabigatran, 600mg metoprolol, 240mg diltiazem, 3.6mg of colchicine, and 3900mg of propafenone. Initial INR and PTT values were beyond the measurable range (>18.2 and >200 respectively). Twelve hours post ingestion, the patient was intubated. There was no intracranial bleeding. On HD2, INR and PTT were 16.4 and 200s. Hemodialysis was initiated. On HD3, INR and PTT declined to 4.3 and 103.1s. On that day a small quantity of coffee-ground emesis was observed in his orogastric tube. On HD4, the patient was extubated, and INR and PTT values declined to 2.0 and 59.8s respectively. The patient demonstrated no further signs of bleeding, and was medically cleared on HD8. During the course of his stay, he was treated with glucagon, calcium gluconate, insulin, dopamine, and norepinephrine.

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An 89 year old male (case #15), normally on 150mg of dabigatran twice daily, ingested 26 tablets of his dabigatran (a 3900 mg dose) in a self-harm gesture. His creatinine was not elevated. INR was initially 9.4 but declined to 1.6 after 3 days. The patient was treated empirically with 6 units of FFP. His hemoglobin declined from 14.7 to a low of 9.3 on HD3 before stabilizing, but he experienced no bleeding or adverse reactions. He was transferred to a psychiatric facility. A 13 month old male diagnosed with pneumonia, was given dabigatran instead of an antibiotic due to pharmacy error. The patient received a total of four 150mg doses over a course of 48 hours. When the error was identified, the patient was admitted for observation. No coagulation studies were available, but he remained asymptomatic and showed no signs of bleeding. He was discharged after approximately 24 hours. Rivaroxaban A 77 year old female (case #4) on a 10mg daily dose of rivaroxaban presented to the ED with hematemesis. The patient was admitted for surgical resolution of a bowel obstruction. She remained stable and was discharged home 8 days after initial presentation. Her peak INR value was 1.4. She was treated with unspecified blood products during surgery, but received none during the remainder of her stay. A 75 year old female (case #6) being treated for DVT developed hematuria 3 days after being started on rivaroxaban 15mg daily and discontinuing her warfarin. She was treated with one

ACCEPTED MANUSCRIPT unit of FFP and vitamin K only. Her INR was initially 14, peaked at 15, and steadily declined to 1.3 after 4 days. The patient remained stable and was discharged the following day.

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A 59 year old male (case #7) with history of atrial fibrillation, hypertension and diabetes intentionally ingested an unknown amount of rivaroxaban and dutasteride in a self-harm gesture. The patient’s peak INR and PTT values were 2.6 and 55s respectively. He was treated with 4 units of FFP and vitamin K. He remained stable and demonstrated no signs of bleeding or adverse reaction. The patient was medically cleared 10 days after admission.

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Discussion

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The American Association of Poison Control Centers 2012 Annual Report of the National Poison Data System shows 7,770 calls were made nationwide to poison control centers regarding anticoagulant medications. There were 219 reported adverse reactions and 9 deaths. There were 3,777 case mentions involving warfarin (excluding rodenticides), with 61 adverse reactions and 0 deaths. There were 920 case mentions involving “other type of anticoagulants” (i.e. not warfarin). Dabigatran and rivaroxaban are potentially represented in this category, but were not specifically mentioned. There were 90 adverse reactions, and 9 deaths in this category (13). A recent study looking at dabigatran exposures reported to the National Poison Data System recorded 802 dabigatran exposures over a 26 month period (14). Some bleeding events were reported, and there were 13 recorded deaths. However, similar to our results there were no major effects and no deaths reported in children.

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The RE-LY clinical trial demonstrated the superiority of dabigatran 150 mg bid to warfarin in preventing stroke and systemic thromboembolis in patients with atrial fibrillation (1.11% vs 1.69% per year). There were similar rates of bleeding events (16.4% vs. 18.2% per year) (15). The ROCKET AF clinical trial for rivaroxaban showed non-inferiority compared to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (1.7% vs. 2.2% per year) and a similar rate of bleeding (14.9% vs. 14.5% per year) (16). Other clinical trials have tested for the non-inferiority of both of these medications for indications including thromboprophylaxis after hip and knee replacements and the treatment of acute venous thromboembolism (15-26). The potential advantages of dabigatran and rivaroxaban compared to warfarin make it likely their use will continue to increase. Understanding how to identify and manage cases of toxicity or misuse of these medications is important. Laboratory Studies Regular monitoring of coagulation studies is not indicated at this time for patients on dabigatran and rivaroxaban. Nevertheless, quantitatively assessing the degree of anticoagulation induced by these medications is important in cases of toxicity. Unfortunately, dabigatran and rivaroxaban do not affect coagulation assays in the same way as traditional anticoagulants.

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PT/INR values respond in a linear-dose-dependent manner to dabigatran. However, the PT/INR is relatively insensitive to the presence of dabigatran, with only mild elevation at therapeutic plasma concentrations. The PTT assay is more sensitive to dabigatran, but does not respond in a linear manner. The degree of elevation tapers off at higher concentrations. The thrombin time assay is the most sensitive to dabigatran and responds in linear-dose-dependent manner. However, it routinely achieves prolongations beyond the measurable range of coagulometers at concentrations of roughly 600ng/ml (three times therapeutic levels), thus limiting its usefulness for quantitatively assessing anticoagulation induced by dabigatran in emergency settings. It is unclear how elevations in these assays correspond with the risk of bleeding (27). Potentially, coagulation studies such as INR and PTT may be useful to rule out toxicity if normal, but caution must be used as several of our cases with only mild INR/PT or PTT elevations still experienced bleeding.

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There were measured elevations in PT/INR and PTT in cases of acute and chronic dabigatran toxicity in our study. Elevations varied from mild to quite large. The degree of elevation did not consistently correspond to the presence or severity of bleeding in our cases.

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Studies have shown rivaroxaban prolongs the PT/INR in a linear dose dependent manner and the PTT in a dose dependent non-linear manner. Both assays are relatively insensitive to rivaroxaban. Furthermore, different reagents of both assays have varying sensitivity to the drug (28-30).

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There were elevations of PT/INR and PTT in cases of acute and chronic rivaroxaban toxicity in our study. The elevations were not as large as those observed in some of the dabigatran cases. This may be a function of dosing, but is unclear. As with dabigatran, the degree of elevation did not consistently correspond to the presence or severity of bleeding. It is possible coagulation parameters might not be as useful for ruling out rivaroxaban toxicity as with dabigatran. Ecarin clotting time (ECT) has also been applied to assess coagulopathy with these agents in some clinical and laboratory settings. ECT takes advantage of ecarin, a component of snake venom that directly activates thrombin. It can serve as an assay for thombin activation, providing a good measure of direct thrombin inhibitor activity, but is generally unaffected by heparin and warfarin therapy. Theoretically ECT could be a good way to measure dabigatran activity, but ECT assays have not been standardized and validated with dabigatran (23). Reversal A variety of in vitro, animal and in vivo human studies have been conducted assessing the effectiveness of potential reversal agents for dabigatran and rivaroxaban toxicity including FFP, 4 factor PCC, FEIBA (Factor eight inhibitor bypassing activity), rFVII (Novoseven), and FIX. (31). There is no rationale for attempting to reverse toxicity of either drug with vitamin K. Dabigatran and rivaroxaban work by directly inhibiting the active site of thrombin and Factor Xa respectively- a completely different mechanism from vitamin K antagonists. Fresh frozen

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plasma is widely available and very effective for reversing warfarin. A murine model demonstrated FFP was effective for slowing intracranial hemorrhage in mice given rivaroxaban but had an inconsistent effect in mice given dabigatran (31-33). It is not clear if FFP would be effective for reversing dabigatran or rivaroxaban coagulopathy in humans.

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Prothrombin complex concentrate (PCC) is available as a 3 or 4 factor product. A study conducted in healthy volunteers showed infusion of Cofact® (an inactivated 4 factor PCC) was effective in restoring normal coagulation parameters (PT and ecarin clotting time [ECT]) after administration of rivaroxaban. Cofact®, however, did not normalize PTT, ECT, TT or ECT after administration of dabigatran (34). Other animal and ex vivo studies have had mixed results, showing PCC corrects some bleeding parameters after dabigatran but not all, and not in a consistent manner. A systematic review determined PCC to be of possible benefit as a dabigatran reversal agent. There is significant evidence for PCC being an effective agent for reversing rivaroxaban (31). Most U.S. hospitals have a four factor, non-activated, PCC that can be tried initially in serious hemorrhage from this agent.

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FEIBA is a four factor PCC that includes an activated form of Factor VII. The previously mentioned systematic review determined FEIBA is likely effective as a reversal agent of both dabigatran and rivaroxaban (31). This is based on a variety of studies including one involving in vitro human plasma spiked with dabigatran that showed correction of TE clot time, an in vivo rat study that showed correction of bleeding time but not TT, PTT or ECT, an ex vivo study in healthy volunteers that showed correction of PTT, and another ex vivo study that showed normalization of thrombin generation (31). In theory, FEIBA should be at least as effective as non-activated PCC for reversal of rivaroxaban, if not more so. It does more to promote thrombin generation compared to inactivated PCCs because of the addition of the activated Factor VII. Studies support this, and showed FEIBA had a more consistent pattern of correcting coagulation parameters in rivaroxaban (31). FEIBA may be the first line agent for dabigatran, and second line if four factor PCC does not work for rivaroxaban associated hemorrhage (35). In primates, FEIBA and recombinant activate factor VIIa independently reversed therapeutic effects of rivaroxaban (36). For all potential factor replacement therapies listed, it should be remembered that they have significant cost and their efficacy in improving outcome has not been proven in humans.

Hemodialysis should be effective in removing dabigatran due to its pharmacokinetics, and may be effective in reversing dabigatran induced coagulopathy. Due to the high degree of renal clearance (80%) of dabigatran, approximately 62-68% can be removed with 4 hours of hemodialysis (37, 38). Studies have also shown charcoal hemoperfusion to also be effective (31). Rivaroxaban is 66% renally cleared, and is dose adjusted based on renal function. Theoretically hemodialysis could aid in clearance of rivaroxaban, especially in cases of renal impairment, but no studies have assessed this method of clearance. Finally, apixaban, another factor Xa inhibitor is now available, and should have similar activity and pharmacokinetics as rivaroxaban. It should be remembered that insertion of a hemodialysis catheter in an anticoagulated patient carries a risk of bleeding.

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Limitations

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This study had several limitations. Data was gathered retrospectively and prospectively, and our study was limited only to cases called into the CPCS. Cases of dabigatran and rivaroxaban exposure or adverse reactions unreported to our system should be taken into consideration. We cannot estimate the incidence of these cases based on our study. Data collection by different poison system staff members may have been recorded in an inconsistent manner. The data provided in each case may be incomplete with missing lab values, treatments or outcomes. Several cases were lost to follow up, and the outcomes of these could have influenced our results. Furthermore, the time laboratory values and treatments were reported to us may not correspond with the time values were actually measured or treatments were given to the patient, making it more difficult to assess the effect of various treatments and the severity of outcomes. In addition, exposures with mixed ingestions were included and this could have confounded results, but known effects from the co-ingestants in our series would not be expected to significantly influence clotting parameters. Limitations of retrospective analysis of poison control system have been characterized in detail elsewhere (39).

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Conclusions

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None of the patients in our case series with accidental extra dose of dabigatran or rivaroxaban reported bleeding or signs of adverse reaction. Provided the excess dose is of a small quantity, it seems it would be safe to observe these cases with no expected adverse reactions.

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Pediatric ingestions of dabigatran reported to us were of small doses. Outcomes were good, and no children experienced bleeding or an adverse event. It is unclear if pharmacokinetics of these drugs differs in children. It may be safe to manage pediatric ingestions of a single or low dose of dabigatran with observation and fall precautions. In deliberate or excessive ingestions, coagulation profiles can be used to confirm ingestion and ensure the drug is being effectively cleared. Early charcoal may be useful for decreasing absorption in self-harm ingestions, but we cannot draw firm conclusions from these cases. In cases of hemorrhage or extremely elevated coagulation profiles, hemodialysis and FEIBA should be considered for dabigatran, and PCC or FEIBA should be considered for rivaroxaban (31), although the efficacy of these therapies is unclear. There were cases of dabigatran toxicity reported to us that clearly corresponded to impaired renal function. Caution should be used when prescribing dabigatran and possible rivaroxaban to the renally impaired (4, 6, 40-42). It is essential to ensure patients are on the proper dose adjusted for creatinine clearance.

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ACCEPTED MANUSCRIPT 14. Conway SE, Schaeffer SE, Harrison, DL: Evaluation of dabigatran exposures reported to poison control centers. Ann Pharmacother. 2014 Mar;48(3):354-60.

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18. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: The RE-MODEL randomized trial. J Thromb Haemost. 2007 Nov;5(11):2178-85.

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19. Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RENOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011 Apr;105(4):721-9.

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CE

20. RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, et al. Oral thrombin inhibitor dabigatran etexilate vs north american enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009 Jan;24(1):1-9. 21. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. 22. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. 23. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: A double-blind, randomised controlled trial. Lancet. 2008 Jul 5;372(9632):31-9. 24. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86.

ACCEPTED MANUSCRIPT 25. Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomatic venous thromboembolism: The continued treatment study (EINSTEIN-extension study). Expert Rev Cardiovasc Ther. 2011 Jul;9(7):841-4.

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26. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): A randomised trial. Lancet. 2009 May 16;373(9676):1673-80.

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27. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010 Jun;103(6):1116-27.

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28. Lindhoff-Last E, Samama MM, Ortel TL, Weitz JI, Spiro TE. Assays for measuring rivaroxaban: Their suitability and limitations. Ther Drug Monit. 2010 Dec;32(6):673-9.

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29. Douxfils J, Mullier F, Loosen C, Chatelain C, Chatelain B, Dogne JM. Assessment of the impact of rivaroxaban on coagulation assays: Laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res. 2012 Dec;130(6):95666.

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30. Harenberg J, Erdle S, Marx S, Kramer R. Determination of rivaroxaban in human plasma samples. Semin Thromb Hemost. 2012 Mar;38(2):178-84.

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31. Lazo-Langner A, Lang ES, Douketis J. Clinical review: Clinical management of new oral anticoagulants: A structured review with emphasis on the reversal of bleeding complications. Crit Care. 2013 Jun 17;17(3):230.

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32. Zhou W, Zorn M, Nawroth P, Butehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013 Mar;44(3):771-8. 33. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011 Dec;42(12):3594-9. 34. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebocontrolled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9. 35. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): What is the evidence? Thromb Haemost. 2013 Oct 17;111(2). 36. Perzborn E, Gruber A, Tinel H, Marzec UM, Buetehorn U, Buchmueller A, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost. 2013 Jul 1;110(1):162-72.

ACCEPTED MANUSCRIPT 37. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: An open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010 Apr;49(4):259-68.

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38. Akwaa F, Spyropoulos AC. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. Curr Treat Options Cardiovasc Med. 2013 Jun;15(3):288-98.

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39. Hoffman RS. Understanding the limitations of retrospective analyses of poison center data. Clin Toxicol (Phila). 2007 Dec;45(8):943-5.

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40. Fellows SE, Rosini JM, Curtis JA, Volz EG. Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency. J Emerg Med. 2013 Feb;44(2):e221-5.

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41. Schattner A, Kozak N, Friedman J. Fatality in a patient treated with dabigatran. Am J Emerg Med. 2013 Feb;31(2):443.e1,443.e2.

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42. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: An open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010 Apr;49(4):259-68.

ACCEPTED MANUSCRIPT TABLE 1: Pharmacokinetic Profiles of Dabigatran and Rivaroxaban Rivaroxaban (Xarelto®)

Thrombin

Factor Xa

3 to 7%

80 to 100% (10mg dose), ~66% (20mg dose)

1 to 2

T1/2 (hr)

12 to 17

Renal Clearance

80%

Protein Binding

35%

RI P

75mg bid for CrCl 15-30 ml/min, 150mg bid for Cr Cl >30 ml/min

PT

ED

Dosing

MA

Tmax (hr)

SC

Bioavailability

92 to 95% 10mg daily, 15 mg daily, 15mg bid, or 20mg od- depending on the indication and degree of renal impairment CYPA34

P-gp Inducers, P-gp Inhibitors

Combined P-gp and strong CYP3A4 inhibitors and inducers

AC

Drug Interactions

66%

No

CE

CYP450

2 to 4

5 to 9 (healthy & young), 11 to 13 (elderly)

NU

Target

T

Dabigatran etexilate (Pradaxa®)

ACCEPTED MANUSCRIPT TABLE 2: Summary of Poison Control Center Guidelines for New Oral Anticoagulant Poisoning a. Check INR/PT/PTT, renal function, CBC and monitor for bleeding. Check every 6 hrs. If 6hr labs normal, can be medical cleared. b. If PT/INR or PTT is elevated- patient should be monitored for 24 hours for bleeding and repeat labs every 6 hrs.

2. Patients with life-threatening bleeding after acute OD or chronic dosing

a. FFP, PCC or PCC + FVII (for patients with closed space bleeding).

SC

RI P

T

1. Acute overdose with no bleeding

AC

CE

PT

ED

MA

NU

b. Consider hemodialysis in all cases of serious bleeding associated with abnormal coagulation studies related to dabigatran.

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

RI P

NU

Elevated INR Elevated PTT

SC

M/F >1.2 >34.0s

T

TABLE 3: Definitions Used for Normal Laboratory Parameters M F Low Creatinine (mg/dL) >1.17 >0.95 Low Hgb (gm/dL) 200

Hematemesis

13

15

F

1.2

38

14

71

M

1.2

15

89

M

9.4

16

49

M

17

81

18

82

ED

Peak Hgb

Maj.

Epistaxis

PT

Peak Cr

T

Peak PTT

RI P

Peak INR

SC

Sex

MA

Case#

NU

Age

CE

Dabigatran

Adverse Rxn Adverse Rxn

11.3

10.3*

Adverse Rxn

5.03

11.8

8.2*

Adverse Rxn*

1.4

10.8

10.3*

Adverse Rxn Acc Ped Ing

12*

Adverse Rxn*

10

3

Adverse Rxn

0.56

9.8

9.2*

Adverse Rxn

Maj.

3.1

14.5

9.7*

Int-Suicide* (1800mg)

-

UTF

0.74

14

39

Rectal Bleeding

UTF

1

153.9

-

Mod.

1.17

14.7

1.1

-

Mod.

1.2

15.9

F

9

-

Maj.

2.1

10.8

10.3*

M

1.93

-

Asx

12.4

12*

AC

13

56

1.08

Int-Suicide* Adverse Rxn 9.3*

Int/Suicide (3900mg) Acc Xtra Dose Adverse Rxn* Acc Xtra Dose* (750mg)

19

69

M

2.2

160

Post Surg GI bleed

Mod.

2.5

20

83

M

1.25

37

Oral- Post Extraction

Mod.

1.4

15.6

21

53

M

11

100

-

Mod.

T

ACCEPTED MANUSCRIPT

12.3

12.2*

Age

Sex

Peak INR

Peak PTT

Bleeding

Peak Hgb

Low Hgb

1

F

86

1.7

39

LGIB, BRBPR

Maj.

2

M

71

2.6

Hematuria

Maj.

12.2

3

F

78

1.5

Vaginal Bleeding

Min. Posb

11.8

11.7

Adverse Rxn

4

F

77

1.4

Hematemesis

Maj.

14.8

11.3

Adverse Rxn

5

F

80

1.4

6

F

75

15

42.3

7

M

59

2.6

55

Asx Maj. UTF

Asymptomatic Major

Unable to Follow

Mod. Moderate Min Posb

Adverse Rxn Int-Suicide* (2625mg)

RI P MA

ED

PT

Hematuria

CE

Key:

44.9

AC

* Co-ingestion

35

Outcome

NU

Rivaroxaban

SC

* Co-ingestion

Pt #

1.47

Adverse Rxn

Minimal Clinical Effects Possible

Asx

Peak Cr

Adverse Rxn

0.9

Adverse Rxn

Acc Xtra Dose (40mg)

15.2

Maj. Min.

Reason

Adverse Rxn 1.1

14

11.3*

Int-Suicide*

ACCEPTED MANUSCRIPT TABLE 7: Outcomes and Demographics Related to Rivaroxaban Exposures IntentionalSuicide n (% tot)

Pediatric

4 (33.3%) 1 (25%) 3 (75%) 62 to 89 83

1 (8.3%) 1 (100%) 59 59

2 (16.7%) 2 (100%) 1.5 1.5

2 (40%) 3 (60%) 5 (100%)

4 (100%) -

1 (100%) -

2 (100%) -

2 1 5 4

1 (20%) 4 (80%)

1 (25%) 3 (75%) -

1 (100%) -

2 (100%) -

Disposition Admit to Non-CCU Admit to CCU Treated/evaluated and released Lost-to-follow-up/other

2 3 5 2

2 (40%) 1 (20%) 2 (40%) -

1 (25%) 3 (75%) -

1 (100%) -

2 (100%)

Labs Elevated INR/Number Reported Elevated PTT/Number Reported Low Hgb/Number Reported Low Hct/Number Reported

7/7 5/5 3/5 4/5

5/5 3/3 2/3 3/3

1/1 1/1 0/1 0/1

1/1 1/1 1/1 1/1

-

PT

AC

CE

Outcome Unable-to-follow No effect/asymptomatic Minimal effects possible Major effect

6 2 3 5

Extra Dose

T

n (% tot)

SC

RI P

5 (41.7%) 1 (20%) 4 (80%) 71 to 86 77

ED

Bleeding No Bleed Documented Gastrointestinal bleed Genitourinary Bleed Number with 1 source of bleeding

12 5 7 1.5 to 89 76

MA

Gen Demographics Number of cases Male Female Age (Range) Age (Median)

n (% tot)

Adverse Reaction n (% tot)

NU

Total

n (% tot)