Thromb Haemost 2017; 117(04): 727-733
DOI: 10.1160/TH16-09-0728
Cellular Haemostasis and Platelets
Schattauer GmbH

Chewing versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in Acute Coronary Syndrome - the CHEERS study

For The PLATIS (Platelets and Thrombosis in Sheba) Study Group
Elad Asher*
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Shir Frydman*
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Moshe Katz
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Ehud Regev
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Avi Sabbag
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Israel Mazin
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Arsalan Abu-Much
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Andrew Kukuy
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Anna Mazo
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Aharon Erez
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Anat Berkovitch
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Michael Narodistky
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Israel Barbash
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Amit Segev
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Roy Beigel
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
,
Shlomi Matetzky
1   Leviev Heart Center, Sheba Medical Center Tel Hashomer, Israel
› Author Affiliations
Further Information

Publication History

Received: 25 September 2016

Accepted after major revision: 31 February 2016

Publication Date:
28 November 2017 (online)

Summary

It was the study objective to evaluate whether chewing a 180 mg loading dose of ticagrelor versus an equal dose of traditional oral administration, enhances inhibition of platelet aggregation 1 hour (h) after administering a ticagrelor loading dose in non-ST elevation myocardial infarction (NSTEMI) patients. Dual anti-platelet therapy represents standard care for treating NSTEMI patients. Ticagrelor is a direct acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Fifty NSTEMI patients were randomised to receive either a chewing loading dose of 180 mg ticagrelor or an equal standard oral dose of ticagrelor. Platelet reactivity was evaluated by VerifyNow at baseline, 1 and 4 h post-loading dose. Results are reported in P2Y12 reaction units. Patients then continued to receive standard 90 mg oral ticagrelor twice daily. Baseline characteristics did not differ between the two groups. P2Y12 reaction units in the chewing group compared with the standard group at 0, 1 and 4 h after ticagrelor loading dose were: 245 vs 239 (p=0.59), 45 vs 130 (p=0.001) and 39 vs 60 (p=0.12), respectively, corresponding to a relative inhibition of platelet aggregation of 83 % vs only 47 % at 1 h (p< 0.001), and 84 % vs 77 % (p=0.59) at 4 h. Major adverse cardiac and cardiovascular events at 30 days were low (2 %), occurring in only one patient in the standard group. In conclusion, chewing a 180 mg ticagrelor loading dose is feasible and facilitates both faster and improved early inhibition of platelet aggregation in NSTEMI patients, compared with a standard oral-loading dose.

Supplementary Material to this article is available online at www.thrombosis-online.com.

* The authors contributed equally to the manuscript.


 
  • References

  • 1 Storey RF, Newby LJ, Heptinstall S. Effects of P2Y1 and P2Y12 receptor antagonists on platelet aggregation induced by different agonists in human whole blood. Platelets 2001; 12: 443-447
  • 2 Anderson JL, Adams CD, Antman EM. et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e179-e347
  • 3 O’Gara PT, Kushner FG, Ascheim DD. et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e78-e140
  • 4 Hamm CW 1, Bassand JP, Agewall S. et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999-3054
  • 5 Steg PG, James SK, Atar D. et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012; 33: 2569-2619
  • 6 Cadroy Y, Bossavy JP, Thalamas C. et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000; 101: 2823-2828
  • 7 Altman R, Scazziota A, Rouvier J, Gonzalez C. Effects of ticlopidine or ticlopidine plus aspirin on platelet aggregation and ATP release in normal volunteers: why aspirin improves ticlopidine antiplatelet activity. Clin Appl Thromb Hemost 1999; 5: 243-246
  • 8 Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 2010; 70: 65-77
  • 9 Birkeland K, Parra D, Rosenstein R. Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor. J Blood Med 2010; 1: 197-219
  • 10 Gurbel PA, Bliden KP, Butler K. et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 22 (120) 2577-2585
  • 11 Mathew ST, Gayathri DS, Prasanth VV, Vinod B. Rationale and role of high loading dose clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Pharmacology & Pharmacy 2012; 3: 481-484
  • 12 Wiviott SD, Trenk D, Frelinger AL. et al. PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial Circulation 2007; 116: 2923-2932
  • 13 Valgimigli M, Tebaldi M, Campo G. et al. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with STsegment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. J Am Coll Cardiol Intv 2012; 5: 268-277
  • 14 Alexopoulos D, Xanthopoulou I, Gkizas V. et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with STsegment-elevation myocardial infarction. Circ Cardiovasc Interv 2012; 5: 797-804
  • 15 Parodi G, Valenti R, Bellandi B. et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013; 61: 1601-1606
  • 16 Franchi F, Rollini F, Cho JR. et al. Impact of escalating loading dose regimens of ticagrelor in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: Results of a prospective randomized pharmacokinetic and pharmacodynamic investigation. J Am Coll Cardiol Cardiovasc Interv 2015; 8: 1457-1467
  • 17 Parodi G, Xanthopoulou I, Bellandi B. et al. Ticagrelor crushed tablets administration in STEMI patients: The MOJITO study. J Am Coll Cardiol 2015; 65: 511-512
  • 18 Feldman M, Cryer B. Aspirin absorption rates and platelet inhibition times with 325-mg buffered aspirin tablets (chewed or swallowed intact) and with buffered aspirin solution. Am J Cardiol 1999; 84: 404-409
  • 19 Mangiacapra F, De Bruyne B, Muller O. et al. High residual platelet reactivity after clopidogrel: extent of coronary atherosclerosis and periprocedural myocardial infarction in patients with stable angina undergoing percutaneous coronary intervention. J Am Coll Cardiol Cardiovasc Interv 2010; 3: 35-40
  • 20 Price MJ, Angiolillo DJ, Teirstein PS. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on thrombosis and safety (GRAVITAS) trial. Circulation 2011; 124: 1132-1137
  • 21 Second International Study of Infarct Survival Collaborative Group. [No authors listed]. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360
  • 22 Husted SE, Storey RF, Bliden K. et al. Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: Results from the ONSET-OFFSET and RESPOND studies. Clin Pharmacokinet 2012; 51: 397-409
  • 23 Michelson AD, Frelinger AL 3rd, Braunwald E. et al. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 2009; 30: 1753-63
  • 24 Bonello L, Laine M, Camoin-Jau L. et al. Onset of optimal P2Y12-ADP receptor blockade after ticagrelor and prasugrel intake in Non-ST elevation acute coronary syndrome. Thromb Haemost 2015; 114: 702-7
  • 25 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175
  • 26 Siller-Matula JM, Trenk D, Schrör K. et al. EPA (European Platelet Academy). Response variability to P2Y12 receptor inhibitors: expectations and reality. J Am Coll Cardiol Cardiovasc Interv 2013; 6: 1111-1128
  • 27 Golino P. Characteristics of new P2Y12 inhibitors: selection of P2Y12 inhibitors in clinical practice. J Cardiovasc Med 2013; Suppl 1: S22-30
  • 28 Alexopoulos D, Xanthopoulou I, Goudevenos J. Effects of P2Y12 receptor inhibition in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2014; 113: 2064-2069
  • 29 Rollini F, Franchi F, Hu J. et al. Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study. J Am Coll Cardiol. 2016 Epub ahead of print
  • 30 Hobl EL, Stimpfl T, Ebner J. et al. Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 2014; 63: 630-635
  • 31 Kubica J, Adamski P, Ostrowska M. et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J 2016; 37: 245-252
  • 32 Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet 2002; 41: 661-680
  • 33 Bartlett JA, van der Voort Maarschalk K. Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine. AAPS PharmSciTech 2012; 13: 1110-1115
  • 34 Navarese EP, Buffon A, Kozinski M. et al. A critical overview on ticagrelor in acute coronary syndromes. QJM 2013; 106: 105-115
  • 35 Shojaei AH. Buccal mucosa as a route for systemic drug delivery: a review. J Pharm Pharm Sci 1998; 1: 15-30
  • 36 Noonan PK, Benet LZ. The bioavailability of oral nitroglycerin. J Pharm Sci 1986; 75: 241-243
  • 37 Mascelli MA, Kleiman NS, Marciniak Jr SJ. et al. Therapeutic heparin concentrations augment platelet reactivity: implications for the pharmacologic assessment of the glycoprotein IIb/IIIa antagonist abciximab. Am Heart J 2000; 139: 696-703
  • 38 Braunwald E, Angiolillo D, Bates E. et al. The Problem of Persistent Platelet Activation in Acute Coronary Syndromes and Following Percutaneous Coronary Intervention. Clin Cardiol 2008; 31 (3 Suppl 1) I17-20
  • 39 Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 2015; 12: 30-47
  • 40 Tantry US, Bonello L, Aradi D. et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischaemia and bleeding. J Am Coll Cardiol 2013; 62: 2261-2273
  • 41 Bhatt DL, Stone GW, Mahaffey KW. et al. CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischaemic events. N Engl J Med 2013; 368: 1303-1313
  • 42 Steg PG, Bhatt DL, Hamm CW. et al. CHAMPION Investigators. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 2013; 382: 1981-1992
  • 43 Cho JR, Rollini F, Franchi F. et al. Pharmacodynamic effects of ticagrelor dosing regimens in patients on maintenance ticagrelor therapy: Results from a prospective, randomized, double-blind investigation. J Am Coll Cardiol Cardiovasc Interv 2015; 8: 1075-1083
  • 44 Roffi M, Patrono C, Collet JP. et al. Task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2016; 37: 267-315