Exploratory Ingestions of Novel Anticoagulants and Antiplatelets: What Is the Risk?

BACKGROUND: Historically, anticoagulants and antiplatelet agents included warfarin and aspirin, respectively. In recent years, numerous novel anticoagulants (eg, direct thrombin inhibitors and factor Xa inhibitors) as well as the adenosine diphosphate receptor antagonists have increased significantly. Little information on the bleeding risk after exploratory ingestion of these agents is available. The primary purpose of this study is to evaluate the bleeding risk of these agents after an exploratory ingestion in children 6 years or younger. METHODS: This retrospective multicenter poison control center study was conducted on calls between 2005 and 2014. The following agents were included: apixaban, clopidogrel, dabigatran, edoxaban, prasugrel, rivaroxaban, or ticagrelor. Bleeding characteristics and treatment rendered were recorded. RESULTS: A total of 638 cases were identified. Most cases involved antiplatelet agents. No patient developed any bleeding complication. The administration of charcoal was independent of the amount of drug ingested. CONCLUSION: Accidental, exploratory ingestions of these agents seem well tolerated, with no patient developing bleeding complications.

Lethal cerebral hemorrhage after ticagrelor intoxication: a specific antidote is urgently needed.

BACKGROUND: Ticagrelor is a direct and reversible competitive antagonist of the P2Y12 receptor and inhibits platelet activation. Although adverse bleeding is common, fatal intoxication has never been documented. CASE DESCRIPTION: A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 d after the massive intake of ticagrelor. Iterative platelet transfusions did not improve his condition. Toxicological analyses by liquid chromatography tandem mass spectrometry (LC-MS/MS) revealed high plasma concentrations of ticagrelor (3343 µg/L) and its active metabolite AR-C124910XX (656 µg/L) 10 h after intake. The approximate ingested dose was extrapolated to 1677 mg. Assessment of ADP-induced platelet aggregation and platelet Vasodilator Stimulated Phosphoprotein phosphorylation (VASP), 2 and 3 d after admission, respectively, showed the persistence of platelet inhibition. DISCUSSION: To the best of our knowledge, no prior fatal cases have been reported and documented with both ticagrelor and AR-C124910XX concentrations. Our findings highlight the need for a specific antidote to manage such complications resulting from ticagrelor overdose.

Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications.

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 (n=9). 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.

Dipyridamole and paracetamol overdose resulting in multi-organ failure.

Dipyridamole intoxication is rare and few reports exist amongst the current literature. A case of dipyridamole and paracetamol overdose is described in a previously healthy 58-year-old woman, which resulted in multi-organ failure requiring dialysis, inotropic support, ventilation and extensive surgical intervention for small bowel ischaemia. This case highlights the dangers of an unusually large overdose of a commonly prescribed drug, and reviews current knowledge of dipyridamole intoxication.

Reversal of thienopyridine-induced platelet dysfunction following desmopressin administration.

Adenosine diphosphate (ADP)-receptor antagonists are widely used for thrombus prevention, although reversing their platelet dysfunction is difficult. This study evaluated the ability of desmopressin to reverse clopidogrel-induced platelet dysfunction. Sprague-Dawley rats received either clopidogrel (30 mg/kg) or placebo, followed 4 h later by saline or desmopressin (0.15, 0.3, or 0.6 µg/kg). Bleeding times and platelet aggregation studies were subsequently performed. A bleeding time >25 min was considered "prolonged." The median bleeding time for clopidogrel-exposed rats was 21 min, vs. 6 min for controls (p < 0.01). Progressively higher doses of 1-deamino-8-D-arginine vasopressin (DDAVP) were associated with a reduced number of rats with prolonged bleeding time (p = 0.001). Higher doses of DDAVP were also associated with a reduction in the median (IQR) bleeding time; 29 (13.5-30) min in rats receiving clopidogrel without DDAVP vs. 19 (12-28) min in rats receiving clopidogrel and 0.6 µg/kg DDAVP. The step-wise dosing of DDAVP resulted in a 54 % reduction in meeting the endpoint of prolonged bleeding time (OR 0.46; p = 0.025; 95 % CI 0.23-0.91). Platelet aggregation was observed in all control rats, but only some of those clopidogrel-treated rats who received 0.6 µg/kg DDAVP. In this model of an ADP-receptor antagonist, DDAVP results in partial reversal of clopidogrel-induced platelet dysfunction.

Toxicokinetics of a dipyridamole (Persantin) intoxication: case report.

We report a case of a 51-year-old woman who was admitted to the hospital after ingestion of large doses of dipyridamole (12 g), temazepam (1 g) and oxazepam (0.2 g) with suicidal intent. The highest dipyridamole concentration that was measured in serum was 9.2 mg/L, which was paralleled by impaired platelet activation. For temazepam and oxazepam, peak serum concentrations were 8.5 and 1.3 mg/L, respectively. The patient was treated with activated charcoal, magnesium sulfate and aminophylline and could be discharged in good physical condition within 17 hours. This is the first report that provides toxicokinetic data and a corresponding pharmacodynamic effect after an intoxication with dipyridamole.

Two cases of oral aspirin overdose.

A 30-year-old woman and a 27-year-old man were found in a parked car after the man had telephoned his father to tell him of their suicide attempt. In spite of emergent hospitalization and intensive care, the woman died. Due to the possibility of his assisting her suicide, medicolegal autopsy and toxicological analysis were performed. On forensic autopsy, no external injuries or pathological findings were detected. The man recovered after 5 days of hospitalization. In spite of a negative toxicological screening test, the police investigation revealed that they may have taken 120 tablets (330 mg/tablet; 39,600 mg total dose) of aspirin (acetylsalicylic acid) orally; therefore, we analyzed the concentrations of acetylsalicylic acid and two kinds of metabolite in specimens obtained at autopsy and on emergent hospitalization using high performance liquid chromatography. Acetylsalicylic acid and/or the two metabolites were found in the woman's specimens. These substances were also present in the man's specimens. It is still unclear why the man survived in spite of what appeared to be a fatal aspirin overdose. It was very straightforward to diagnose aspirin poisoning in these cases; however, we have to be aware of poisoning by drugs which are not included in simple drug screening examinations.

Massive GI bleeding due to accidental ASA inhalation.

This report describes a 38-year-old man admitted to hospital for a massive rectal bleeding and syncope. He was known to have idiopathic thrombocytopenia but he had never complained of bleeding until he was admitted to hospital with uncontrolled hemorrhage. Upper and lower endoscopic examination, performed 6 hours after occurrence of bleeding, were negative for ulcers or other bleeding lesions. However, capsule endoscopy did detect diffuse areas of petechial hemorrhage and erosions in the small bowel. Thromboelastography performed on the day of admission showed a marked decrease in platelet aggregation rate, that normalized two days after. The patient recovered with conservative treatment only. Thorough questioning did not evidence relevant events apart from inhalation of a massive quantity of acetylsalicylic acid: the patient, working as a farmer, had prepared, without protection, fodder for the animals containing a great amount of acetylsalicylic acid. Bleeding had started few hours thereafter. After recovery, bleeding did not recur despite persistent thrombocytopenia.

Pattern of clopidogrel exposures reported to Texas poison centers during 1998-2004.

BACKGROUND: Information on the management of potentially adverse exposures to clopidogrel is limited. METHODS: This study examined the distribution of 582 clopidogrel exposures reported to Texas poison control centers during 1998-2004. RESULTS: Eighty-four percent of cases with a reported dose having a dose < or = 150 mg. Management of 65% of the exposures occurred on site. Of those exposures with a final medical outcome, 73% were classified as no effect. Of those exposures to clopidogrel alone, the most frequent adverse clinical effects were vomiting (2.4%) and dizziness (2.4%). The most frequent treatments were decontamination by dilution (30%), food (12%), and activated charcoal (7%). CONCLUSION: In the majority of potentially adverse clopidogrel exposures reported to poison control centers the doses are twice the recommended dosage or less. The outcome of such exposures are generally favorable, with few adverse clinical effects occurring.

The role of continuous renal replacement therapy in the treatment of poisoning.

Extracorporeal elimination of drugs and toxins is a critical component in the management of poisonings, though specific techniques and indications remain a matter of debate. Conventional hemodialysis is frequently the treatment of choice because of its widespread availability and proven effectiveness for certain drugs and toxins. With the increased availability of continuous renal replacement therapy (CRRT) modalities, there is yet another therapeutic option, but one that has yet to find a definitive role in this field. The continuous nature of these therapies is attractive for the management of acute renal failure, but the relatively slower clearance rates as compared to conventional hemodialysis is a distinct drawback in patients with acute xenobiotic-induced toxicity. There are abundant case reports as well as a few small case series in the medical literature documenting the use of CRRT, but specific techniques and the clinical outcomes vary considerably. Therefore one cannot draw definitive conclusions regarding benefit. Some patients, particularly those who are hemodynamically unstable and are not candidates for conventional hemodialysis, may warrant a trial of CRRT. However, at the present time, routine use for the treatment of poisoning is not supported. Controlled trials to better clarify its role would be beneficial, though such studies would be extremely difficult to conduct in this field. We believe that the intelligent application of extracorporeal modalities requires a thorough knowledge of drug pharmacokinetics, of the techniques utilized, and a skeptical analysis of the available literature.

Suicide attempt with clopidogrel.

We report the case of a 49-year-old male who took an overdose of 1650 mg of clopidogrel with suicidal intent. The patient developed abnormalities of platelet aggregation, but never developed symptoms. Clopidogrel is a commonly prescribed drug. Reports of overdose of clopidogrel were very rarely reported in the literature.