Ticagrelor and primidone interaction masquerading as dual antiplatelet therapy noncompliance
Abstract
Ticagrelor and aspirin is a common dual antiplatelet therapy regimen for patients who undergo percutaneous coronary intervention. Despite its ability to significantly reduce cardiovascular complications, ticagrelor response may be altered by other medications causing subtherapeutic effects. Traditionally, ticagrelor is thought to have fewer drug–drug interactions compared to other thienopyridine antiplatelet medications such as clopidogrel. Primidone, metabolized into phenobarbital, is a strong CYP-3A inducer that can reduce serum concentrations of ticagrelor resulting in ineffective antiplatelet therapy. We present a 67-year-old male who suffered in-stent thrombosis after percutaneous intervention possibly due to the interaction between primidone and ticagrelor.
Plain language summary
Ticagrelor and aspirin is a common antiplatelet regimen for patients who undergo coronary intervention and stent implantation. Ticagrelor is typically less associated with drug–drug interactions; however, our case illustrates an interaction between ticagrelor and primidone causing acute in-stent thrombosis to recently implanted drug-eluting stents.
Papers of special note have been highlighted as: • of interest
References
- 1. . Primidone. In: StatPearls. StatPearls Publishing (2022). www.ncbi.nlm.nih.gov/books/NBK562297/
- 2. . Efficacy of primidone in essential tremor. Neurology 36(1), 121–124 (1986).
- 3. . The influence of diphenylhydantoin on primidone metabolism. Arch. Neurol. 30(3), 259–262 (1974). • It is not common knowledge that primidone metabolizes into phenobarbital, making it a strong CYP altering medication.
- 4. . Chapter 10. In: Physiologically Based Pharmacokinetic Modeling: Science and Applications. John Wiley & Sons, NJ, USA, 292–293 (2005).
- 5. . Therapeutic drug monitoring of primidone and phenobarbital. Therapie 67(4), 381–390 (2012).
- 6. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N. Engl. J. Med. 371(23), 2155–2166 (2014).
- 7. Oral antiplatelet therapy after acute coronary syndrome: a review. J. Am. Med. Assoc. 325(15), 1545–1555 (2021).
- 8. . Ticagrelor. Profiles Drug Subst. Excip. Relat. Methodol. 47, 91–111 (2022).
- 9. Long-term use of ticagrelor in patients with prior myocardial infarction. N. Engl. J. Med. 372(19), 1791–1800 (2015).
- 10. . The effect of ticagrelor on the metabolism of midazolam in healthy volunteers. Clin. Ther. 35(7), 1025–1037 (2013).
- 11. . A review of the effects of ticagrelor on adenosine concentration and its clinical significance. Pharmacol. Rep. 73(6), 1551–1564 (2021).
- 12. Metabolism of ticagrelor in patients with acute coronary syndromes. Sci. Rep. 8(1), 11746 (2018). • Ticagrelor is shown to be affected by CYP inducers such as rifampin, which can possibly be extrapolated to this case.
- 13. . Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy 34(10), 1077–1090 (2014).
- 14. . Clopidogrel–drug interactions. J. Am. Coll. Cardiol. 57(11), 1251–1263 (2011).
- 15. Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy. Ther. Clin. Risk Manag. 11, 449–467 (2015).
- 16. . Clopidogrel resistance: a new chapter in a fast-moving story. Circulation 109(25), 3064–3067 (2004). • Clopidogrel resistance is documented within the literature with concerns of many patients who are at risk for dual antiplatelet therapy failure.
- 17. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109(25), 3171–3175 (2004).
- 18. . Clinical implications of clopidogrel resistance. Thromb. Haemost. 100(2), 196–203 (2008). • Studies may suggest that many factors can contribute to such ‘resistance’, and it should be better characterized as variable therapeutic effect rather than resistance.
- 19. . The use of the VerifyNow system to monitor antiplatelet therapy: a review of the current evidence. Platelets 19(7), 479–488 (2008).
- 20. . Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am. Heart J. 164(1), 35–42 (2012). • VerifyNow assay initially was intended for clopidogrel only, however, may also be useful for other P2Y12 inhibitors.
- 21. Different influences of hematocrit on the results of two point-of-care platelet function tests, the VerifyNow assay and multiple electrode platelet aggregometry. PLOS ONE 9(11), e114053 (2014).
- 22. . Hematocrit alters VerifyNow P2Y12 assay results independently of intrinsic platelet reactivity and clopidogrel responsiveness. J. Thromb. Haemost. 11(10), 1814–1822 (2013).
- 23. Determinants of high on-treatment platelet reactivity and agreement between VerifyNow and Multiplate assays. Scand. J. Clin. Lab. Invest. 77(3), 190–198 (2017).
- 24. Baseline anemia in patients undergoing percutaneous coronary intervention after an acute coronary syndrome-A paradox of high bleeding risk, high ischemic risk, and complex coronary disease. J. Interv. Cardiol. 30(5), 491–499 (2017).
- 25. P2Y12 inhibitor monotherapy or dual antiplatelet therapy after complex percutaneous coronary interventions. J. Am. Coll. Cardiol. 81(6), 537–552 (2023).
- 26. Brilinta™ (ticagrelor) Tablets: A P2Y(12) platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). PT 37(4 section 2), 4–18 (2012). https://pubmed.ncbi.nlm.nih.gov/22605912/ • P2Y12 monotherapy may provide an ongoing discussion on platelet inhibition postpercutaneous coronary intervention, especially for patients who are high risk for bleeding.