Ticagrelor

Publication Details

OVERVIEW

Introduction

Ticagrelor is an oral antiplatelet drug that is used with low dose aspirin to decrease the risk of myocardial infarction and stroke in patients with acute coronary syndromes. Ticagrelor has been linked to rare instances of hypersensitivity reactions accompanied by mild liver injury.

Background

Ticagrelor (tye ka' grel or) is a non-thienopyridine, reversible inhibitor of adenosine diphosphate (ADP) receptors (P2Y 12) on platelets and is used to decrease the risk of recurrent coronary thromboses in patients who undergo interventions during an acute coronary syndrome. Activated platelets release ADP which binds to ADP platelet receptors, causing activation of intracellular glycoprotein IIb/IIIA complex which triggers platelet adherence and aggregation. The aggregation of platelets plays an important role in the growth of atheromatous plaques, which can lead to coronary, cerebral and peripheral arterial occlusions. In clinical trials, ticagrelor therapy during acute coronary events (unstable angina and myocardial infarction) has been shown to decrease the frequency of recurrence of myocardial infarction and stent thrombosis. Ticagrelor was approved for use in the United States in 2011 and has been used in limited numbers of patients for a limited time only. Current indications are reduction of recurrent cardiovascular events in patients with acute coronary syndromes. Ticagrelor is available in 90 mg tablets under the commercial name Brilinta. The usual maintenance dose is 90 mg twice daily in combination with daily low dose aspirin (<100 mg). Side effects are not common, but can include bleeding (12%), dyspnea (14%), headaches, nausea, diarrhea, hypotension and hypersensitivity reactions. Rare but potentially severe adverse reactions include severe bleeding, rhabdomyolysis, complications of drug-drug interactions, angioedema and hypersensitivity reactions.

Hepatotoxicity

In several large clinical trials, ticagrelor was not associated with serum enzyme elevations during therapy and no instances of clinically apparent liver injury were reported. While there have been isolated reports of transient and mild serum enzyme elevations during ticagrelor therapy, these have been short lived and asymptomatic. In addition, since marketing and release, there have been no reports of isolated clinically apparent liver injury or jaundice associated with ticagrelor therapy and hepatotoxicity is not mentioned in the product label. On the other hand, there have been several reports of jaundice and liver injury associated with rhabdomyolysis and with thrombotic thrombocytopenic purpura that represented secondary effects of these severe adverse events. Thus, significant liver injury due to ticagrelor occurs but has occurred largely in association with other life-threatening complications.

Likelihood score: D (possible rare cause of liver injury due to complications of severe allergic reactions or drug-drug interactions).

Mechanism of Injury

Ticagrelor, unlike clopidogrel, does not require metabolic activation for its antiplatelet effects. Ticagrelor is metabolized in the liver predominantly via CYP 3A4 and it should be used with caution in patients taking CYP 3A4 inhibitors (such as ketoconazole, clarithromycin, atazanavir and nefazodone), which can increase serum levels, or CYP 3A4 inducers (such as rifampin, dexamethasone and phenytoin) which can decrease drug levels.

Outcome and Management

There is little evidence that ticagrelor can cause liver injury or has any cross sensitivity to other antiplatelet agents, so that switching from clopidogrel or prasugrel after clinically apparent liver injury is probably safe.

Drug Class: Antithrombotic Agents, Antiplatelet Agents

Other Drugs in the Subclass, Antiplatelet Agents: Aspirin, Cangrelor, Clopidogrel, Dipyridamole, Prasugrel, Ticlopidine, Vorapaxar

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Ticagrelor – Brilinta®

DRUG CLASS

Antithrombotic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 25 September 2020

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    (Textbook of hepatotoxicity published in 1999; ticlopidine, but not clopidogrel, prasugrel or ticagrelor is discussed).
  • De Marzio DH, Navarro VJ. Antiplatelet agents. Hepatotoxicity of cardiovascular and antidiabetic drugs: antihypertensives. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 527-8.
    (Review of hepatotoxicity of antiplatelet drugs discusses ticlopidine, clopidogrel and prasugrel, but does not mention ticagrelor).
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    (Textbook of pharmacology and therapeutics).
  • Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038–47. [PubMed: 16476694]
    (Among 200 patients with atherosclerosis treated with one of 4 doses of ticagrelor or clopidogrel for 28 days, inhibition of platelet aggregation was greater with higher doses of ticagrelor and the most common adverse events were bleeding, dyspnea, dizziness and headache; "no notable time- or treatment-related changes in any ... clinical chemistry parameters ... were observed").
  • Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF. DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007;50:1844–51. [PubMed: 17980250]
    (Among 990 patients with an acute coronary syndrome treated with one of 2 doses of ticagrelor or clopidogrel for 4-12 weeks, bleeding episodes were similar in the three groups [9.8% and 8.0% vs 8.1%]; no mention of ALT elevations or hepatotoxicity).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to antiplatelet agents).
  • Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, et al. PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57. [PubMed: 19717846]
    (Among 18,624 patients with acute coronary syndrome treated with ticagrelor or clopidogrel, deaths from vascular cases within 12 months were less with ticagrelor [9.8% vs 11.7%], while major bleeding rates were similar [11.6% vs 11.2%]; no mention of hepatotoxicity or ALT elevations).
  • Mohammad RA, Goldberg T, Dorsch MP, Cheng JW. Antiplatelet therapy after placement of a drug-eluting stent: a review of efficacy and safety studies. Clin Ther. 2010;32:2265–81. [PubMed: 21353100]
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    (Subgroup analysis of 1261 patients who underwent coronary artery bypass grafting and were treated with ticagrelor or clopidogrel; no discussion of ALT elevations or hepatotoxicity).
  • James SK, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, Katus H, et al. PLATO Study Group. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ. 2011;342:d3527. [PMC free article: PMC3117310] [PubMed: 21685437]
    (Among 5216 patients with acute coronary syndrome treated with ticagrelor or clopidogrel with a planned noninvasive treatment, cardiovascular death was lower with ticagrelor [12% vs 14.3%], while major bleeding episodes were greater [11.9% vs 10.3%]; no mention of ALT elevations or other adverse events).
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    (Pharmacokinetic study in 20 volunteers, 10 with compensated cirrhosis, found minimally higher exposure after a single dose of ticagrelor in patients with liver disease, but not enough to recommend dose adjustment; no side effects or worsening of liver chemistry results).
  • Ticagrelor (Brilinta)--better than clopidogrel (Plavix)? Med Lett Drugs Ther. 2011;53(1372):69–70. [PubMed: 21897348]
    (Concise review of the pharmacology, efficacy and safety of ticagrelor shortly after its approval in the US mentions side effects of bleeding, dyspnea, bradyarrhythmias and increases in uric acid and creatinine [effects probably related to stimulation of adenosine receptors]; no mention of ALT elevations or hepatotoxicity).
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    (Guidelines on use of antiplatelet agents including aspirin, clopidogrel, prasugrel and ticagrelor mentions that ticagrelor was found to be more effective than clopidogrel in one study without an increased rate of bleeding; no mention of other side effects, ALT elevations or hepatotoxicity).
  • Li H, Butler K, Yang L, Yang Z, Teng R. Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese subjects: an open-label, sequential, two-cohort, single-centre study. Clin Drug Investig. 2012;32:87–97. [PubMed: 22168538]
    (In a pharmacokinetic study of ticagrelor in 26 healthy volunteers, two patients developed asymptomatic serum ALT elevations [1.25 and 3 times ULN] without change in bilirubin or alkaline phosphatase within 3 days of starting ticagrelor and lasting for 10 days after stopping).
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    (Review of pharmacology, efficacy and safety of ticagrelor in comparison to other antiplatelet agents; no mention of hepatotoxicity or ALT elevations during therapy).
  • DiNicolantonio JJ, Serebruany VL. Comparing the safety of ticagrelor versus clopidogrel: insights from the FDA reports. Ther Adv Cardiovasc Dis. 2013;7:5–9. [PubMed: 23393061]
    (The FDA analysis of trials of ticagrelor reported that patients with preexisting liver disease were more likely to have serious adverse events on ticagrelor than clopidogrel, including death [3.1% vs 0.9%] and major bleeds [11.2% vs 8.7%], the reasons for which were not clear).
  • Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann A, Maya J, Husted S, et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J. 2014;35(31):2083–93. [PMC free article: PMC4132637] [PubMed: 24727884]
    (Retrospective analysis of data from the PLATO trial of ticagrelor vs clopidogrel in 18,624 patients with acute coronary syndrome found similar rates of bleeding with both agents; no mention of ALT elevations or hepatotoxicity).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]
    (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, none were attributed to ticagrelor).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, two were attributed to antithrombotic agents, one to prasugrel and one to dalteparin; none were due to ticagrelor).
  • Banakh I, Haji K, Kung R, Gupta S, Tiruvoipati R. Severe rhabdomyolysis due to presumed drug interactions between atorvastatin with amlodipine and ticagrelor. Case Rep Crit Care. 2017;2017:3801819. [PMC free article: PMC5463112] [PubMed: 28630772]
    (74 year old woman developed rhabdomyolysis 2 months after starting ticagrelor having been on atorvastatin for years with complications of septic shock, renal failure and acute hepatic necrosis [bilirubin 3.1 to 9.8 mg/dL, 746 to 1605 U/L, Alk P 260 to 325 U/L, INR 1.8 to 2.0, CPK >90,000 IU/L], with prolonged ICU stay but ultimate resolution of renal and liver abnormalities).
  • Bellosta S, Corsini A. Statin drug interactions and related adverse reactions: an update. Expert Opin Drug Saf. 2018;17:25–37. [PubMed: 29058944]
    (Summary and review of drug-drug interactions including ticagrelor, a CYP3A4 and P-pg substrate and weak inhibitor which can cause an increase in atorvastatin plasma levels).
  • Wang X, Zhang S, Li L, Hua J, Zhu L, Li L, Zhang G. Ticagrelor-induced thrombotic thrombocytopenic purpura: A case report and review of the literature. Medicine (Baltimore). 2018;97:e11206. [PMC free article: PMC6039671] [PubMed: 29952973]
    (87 year old man with a history of acute myocardial infarction developed thrombotic thrombocytopenic purpura 2 months after starting ticagrelor [platelets 3,000, hematocrit 22.3%, bilirubin 16.0 mg/dL, ALT 3947 U/L, Alk P 59 U/L, protime 26.3 sec], with spontaneous improvement but recurrence on restarting ticagrelor leading to multiorgan failure and death).
  • Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J. Richardt Get al.; ISAR-REACT 5 Trial Investigators. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019;381:1524–34. [PubMed: 31475799]
    (Among 4018 patients with acute coronary syndromes treated with ticagrelor or prasugrel for one year, major cardiovascular events were less with prasugrel [6.9% vs 9.3%], but major bleeding event rates were similar [4.8% vs 5.4%]; no mention of ALT elevations or hepatotoxicity).
  • Navarese EP, Khan SU, Kołodziejczak M, Kubica J, Buccheri S, Cannon CP, Gurbel PA, De Servi S, Budaj A, Bartorelli A, Trabattoni D, Ohman EM, Wallentin L, Roe MT, James S. Comparative efficacy and safety of oral P2Y inhibitors in acute coronary syndrome: network meta-analysis of 52 816 patients from 12 randomized trials. Circulation. 2020;142:150–60. [PMC free article: PMC7489363] [PubMed: 32468837]
    (Metaanalysis of 12 randomized controlled trials in 52,816 patients comparing 3 antiplatelet agents found that prasugrel and ticagrelor had lower rates of cardiovascular mortality and stent thrombosis than clopidogrel, but had higher rates of major bleeding episodes; no mention of ALT elevations or hepatotoxicity).
  • Tarantini G, Mojoli M, Varbella F, Caporale R, Rigattieri S, Andò G, Cirillo P, et al.; DUBIUS Investigators, on behalf of the Italian Society of Interventional Cardiology (SICI-GISE). Timing of oral P2Y inhibitor administration in non-ST elevation acute coronary syndrome. J Am Coll Cardiol 2020: S0735-1097(20)36444-5. Epub ahead of print.
    (Among 1449 patients undergoing coronary angiography treated with prasugrel or ticagrelor, rates of a combined clinical efficacy endpoint were similar in the two groups; no mention of ALT elevations or hepatotoxicity).