Risk of Bleeding After Antiplatelet or Oral Anticoagulant Overdose

What is the risk of bleeding after an acute (or acute-on-chronic) overdose of the newer oral antiplatelet and anticoagulant agents? A new study in the Annals of Emergency Medicine set out to answer this question.

What They Did

• Retrospective study of poison control center calls involving patients with intentional ingestions of novel antiplatelet or anticoagulant medications (acute or acute-on-chronic)
• Data pooled from 7 poison control centers in 4 states
• Primary outcome measurement: presence of bleeding during the index call or during the follow-up period (bleeding was defined in the methods)
• The narrative sections of each chart were reviewed in addition to the electronically-collected, dropdown-style data points (this adds important information not always available from the poison center database review alone)

What They Found

• 322 cases over 10 years
  • 260 (80.7%) clopidogrel
  • 40 (12.4%) rivaroxaban
  • 9 (2.8%) dabigatran
  • 5 (1.6%) prasugrel
  • 3 (0.93%) ticagrelor
  • 2 (0.62%) ticlopidine – no longer on the U.S. market
• Bleeding developed in 16 (4.9%) cases (7 clopidogrel, 6 rivaroxaban, 2 dabigatran, 1 apixaban)
  • Major bleeding: 9 cases, minor: 3 cases, trivial: 4 cases

Some Thoughts

1. This article addresses is an important question that poison center records may help us answer, in part. The authors do a nice job of explaining some of the limitations of the study. Dr. Robert Hoffman (@bobhoffmd) wrote a piece back in 2007 that further helps interpret these data (Clin Toxicol 2007).
2. Because of voluntary reporting, 322 cases likely underrepresents the total number of overdoses during the study period. The denominator is unknown, which makes the true incidence of bleeding difficult to estimate.
3. The authors rightly point out that though the study period covered 10 years, it ended December 31, 2014. In the 2 years following, it is likely that the newer anticoagulants were prescribed (and overdosed on) even more, which may have added important insight toward the study conclusions.
4. Data points that could add important insight:
   • How many patients were on concurrent aspirin therapy?
   • What co-morbidities existed that increased risk of bleeding?
   • How many patients who overdosed were therapeutically on the other agent (eg, overdosed on rivaroxaban but are therapeutically on clopidogrel)?
   • What was the cause of bleeding and was it unrelated to the overdose?
5. Without some laboratory confirmation that an overdose took place, we may be underestimating the prevalence of bleeding after an overdose.
6. Follow-up calls were made at least 4 hours after the initial call. This probably increased the capture rate for the outcomes being assessed (eg, bleeding). However, the bleeding risk may be high for up to 24 hours (or even longer) for some of these agents. Rivaroxaban, for example, is known to have a prolonged absorption time.
7. How many patients received charcoal? There is emerging evidence that charcoal may be effective in reducing rivaroxaban absorption even if given 8 hours after a dose (Clin Pharmacokinet 2017).

Application to Clinical Practice

It is certainly helpful to have an estimate of the potential risk of bleeding (~5%) after an antiplatelet or novel oral anticoagulant overdose. Even with this data, it is difficult to plan patient dispositions without knowing the denominator of all overdoses and without laboratory confirmation demonstrating at least an estimated supratherapeutic level at some point within 24 hours of the ingestion.

Reference

Levine M, et al. Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications. Ann Emerg Med. 2017 Oct 9. Epub ahead of print. PMID 29032872