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Figure 1.
CONSORT Flow Diagram
CONSORT Flow Diagram

GP IIBIIA indicates glycoprotein IIB/IIIA; LD, loading dose; STEMI, ST-segment elevation myocardial infarction.

Figure 2.
Inhibition of Platelet Aggregation in the Chewing Group vs the Standard Group
Inhibition of Platelet Aggregation in the Chewing Group vs the Standard Group

IPA indicates inhibition of platelet aggregation; LD, loading dose; PRU, P2Y12 reaction units.

Table.  
Baseline Characteristics, Revascularization, and TIMI Flow of Patients in the Chewing Group vs the Standard Group
Baseline Characteristics, Revascularization, and TIMI Flow of Patients in the Chewing Group vs the Standard Group
1.
Butler  K, Teng  R.  Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers.  Br J Clin Pharmacol. 2010;70(1):65-77.PubMedGoogle ScholarCrossref
2.
Birkeland  K, Parra  D, Rosenstein  R.  Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor.  J Blood Med. 2010;1:197-219.PubMedGoogle Scholar
3.
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(15):1601-1606.PubMedGoogle ScholarCrossref
4.
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.  JACC Cardiovasc Interv. 2015;8(11):1457-1467.PubMedGoogle ScholarCrossref
5.
Parodi  G, Xanthopoulou  I, Bellandi  B,  et al.  Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study.  J Am Coll Cardiol. 2015;65(5):511-512.PubMedGoogle ScholarCrossref
6.
Asher  E, Frydman  S, Katz  M,  et al; For The PLATIS (Platelets and Thrombosis in Sheba) Study Group.  Chewing vs swallowing ticagrelor to accelerate platelet inhibition in acute coronary syndrome: the CHEERS study.  Thromb Haemost. 2017;117(4):727-733.PubMedGoogle ScholarCrossref
7.
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.  JACC Cardiovasc Interv. 2010;3(1):35-40.PubMedGoogle ScholarCrossref
8.
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(10):1132-1137.PubMedGoogle ScholarCrossref
9.
Bhatt  DL, Stone  GW, Mahaffey  KW,  et al; CHAMPION PHOENIX Investigators.  Effect of platelet inhibition with cangrelor during PCI on ischemic events.  N Engl J Med. 2013;368(14):1303-1313.PubMedGoogle ScholarCrossref
10.
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(9909):1981-1992.PubMedGoogle ScholarCrossref
11.
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(7):630-635.PubMedGoogle ScholarCrossref
12.
Mascelli  MA, Kleiman  NS, Marciniak  SJ  Jr, Damaraju  L, Weisman  HF, Jordan  RE.  Therapeutic heparin concentrations augment platelet reactivity: implications for the pharmacologic assessment of the glycoprotein IIb/IIIa antagonist abciximab.  Am Heart J. 2000;139(4):696-703.PubMedGoogle ScholarCrossref
13.
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-I20.PubMedGoogle ScholarCrossref
Brief Report
December 2017

Effect of Chewing vs Swallowing Ticagrelor on Platelet Inhibition in Patients With ST-Segment Elevation Myocardial Infarction: A Randomized Clinical Trial

Author Affiliations
  • 1Leviev Heart Center, Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel
JAMA Cardiol. 2017;2(12):1380-1384. doi:10.1001/jamacardio.2017.3868
Key Points

Question  Is chewing a loading dose of ticagrelor, 180 mg, vs traditional oral administration of an equal dose enhance platelet inhibition at 30 minutes and 1 hour after loading dose administration in patients with ST-segment elevation myocardial infarction?

Findings  In this randomized clinical trial, chewing a loading dose of ticagrelor, 180 mg, in patients with ST-segment elevation myocardial infarction was feasible and facilitated better early platelet inhibition compared with standard oral loading dose.

Meaning  In patients with ST-segment elevation myocardial infarction, chewing a loading dose of ticagrelor, 180 mg, may be warranted.

Abstract

Importance  Dual anti-platelet therapy represents standard care for treating patients with ST-segment elevation myocardial infarction (STEMI). Ticagrelor is a direct-acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation.

Objective  To evaluate whether chewing a loading dose (LD) of ticagrelor, 180 mg, vs traditional oral administration of an equal dose enhances platelet inhibition at 30 minutes and 1 hour after LD administration in patients with STEMI.

Design, Setting, and Participants  A randomized clinical trial was conducted in adults aged 30 to 87 years from May to October 2016 in a large tertiary care center. Analyses were intention-to-treat.

Interventions  Fifty patients with STEMI were randomized to either chewing an LD of ticagrelor, 180 mg, or standard oral administration of an equal dose.

Main Outcomes and Measures  P2Y12 reaction units were evaluated using VerifyNow (Accumentrics) at baseline, 30 minutes, 1 hour, and 4 hours after LD.

Results  Baseline characteristics were similar in both groups. The mean (SD) of P2Y12 reaction units in the chewing group compared with the standard group at baseline, 30 minutes, 1 hour, and 4 hours after ticagrelor LD were 224 (33) vs 219 (44) (95% CI, −16.77 to 27.73; P = .26), 168 (78) vs 230 (69) (95% CI, −103.77 to −19.75; P = .003), 106 (90) vs 181 (89) (95% CI, −125.15 to −26.29; P = .005), and 43 (41) vs 51 (61) (95% CI, −36.34 to 21.14; P = .30), respectively. Platelet reactivity in the chewing group was significantly reduced by 24% at 30 minutes after LD (95% CI, 19.75 to 103.77; P = .001). The relative inhibition of platelet aggregation in the chewing vs the standard group were 51% vs 10% (95% CI, 13.69 to 67.67; P = .005) at 1 hour and 81% vs 76% (95% CI, −12.32 to 16.79; P = .24) at 4 hours, respectively. Major adverse cardiac and cardiovascular event rate at 30 days was low (4%) and occurred in 1 patient in each group (95% CI, 0.06 to 16.93; P > .99).

Conclusions and Relevance  Chewing an LD of ticagrelor, 180 mg, in patients with STEMI is feasible and facilitates better early platelet inhibition compared with a standard oral LD. Larger studies are warranted to see if our preliminary findings translate into clinical outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT02725099

Introduction

Ticagrelor is an orally administered cyclopentyl triazolopyrimidine that reversibly and directly inhibits the platelet P2Y12 receptor1 and does not require metabolic activitation for inhibition of platelet aggregation (IPA).2 Given the higher risk of peri-procedural thrombotic events in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), there is a need to achieve IPA more promptly. Nevertheless, when administering a P2Y12 inhibitor in patients with STEMI, the time to peak IPA may take several hours.3 Although platelet reactivity is a surrogate, the delay in platelet inhibition in response to a ticagrelor loading dose (LD) in patients with STEMI has been related to several factors and primarily to an impaired intestinal absorption.4 Several studies have tried to overcome this problem with increasing the dosing regimen and crushing tablets.5 Although chewing ticagrelor has been shown to be more efficient for patients with IPA with acute coronary syndrome/non-STEMI,6 to our knowledge, there are no studies that have specifically assessed the efficacy and safety of chewing ticagrelor in patients with STEMI. The aim of this study was to investigate whether chewing ticagrelor is associated with more favorable platelet inhibitory effects compared with the conventional way of swallowing whole tablets in patients with STEMI undergoing PPCI.

Methods

This prospective study was conducted from May to October 2016 and comprised 50 consecutive patients with STEMI who underwent PPCI. Patient treatment has been described previously.6 In brief, all patients were treated with a ticagrelor LD (180 mg per day) and aspirin (100 mg per day). On admission, patients were randomized to either the chewing group (patients were asked to actively chew the tablets and not to swallow them and did not receive water) or the traditional swallowing group (standard group of the 180-mg ticagrelor LD). Patients then continued to receive oral ticagrelor (90 mg twice daily) in the conventional swallowing way. Exclusion criteria have been described previously.6 Baseline characteristics and in-hospital therapy were prospectively recorded. The study was approved by the local institutional review board, and patients provided written informed consent. The full trial protocol is available in Supplement 1.

Platelet Reactivity Testing

Blood samples for platelet reactivity were collected at baseline (before ticagrelor LD), 30 minutes, 1 hour, and 4 hours after ticagrelor LD. Platelet reactivity was performed using VerifyNow (Accumetrics) and was reported in P2Y12 reaction units (PRU).7 High treatment-related platelet reactivity (HPR) was defined as a PRU of more than 208.8 All patients were then treated at the discretion of the treating physicians.

End Points

The primary end point was residual platelet reactivity by PRU at 1 hour after ticagrelor LD. Secondary end points were (1) platelet reactivity at each point; (2) rates of HPR; (3) major adverse cardiac and cerebrovascular events (death, myocardial infarction, urgent revascularization, stroke/transient ischemic attack) at 30 days; (4) major or minor bleeding (using Thrombolysis in Myocardial Infarction criteria); and (5) occurrence of dyspnea and/or symptomatic bradycardia.

Statistical Analysis

The primary and secondary end points were assessed based on an intention-to-treat basis. Assuming an absolute 15% difference in the PRU between the 2 groups at 1 hour after ticagrelor LD with a common SD of 10%, 20 patients would need to be enrolled in each arm to obtain a 95% power and a 2-sided α of .05. Considering a dropout rate of approximately 5%, we estimated that a total of 50 patients would need to be randomized to ensure complete data availability for analysis. The t test was used for evaluating the difference in prespecified end points. If the assumption of normality was violated, a nonparametric test (Mann-Whitney U or Wilcoxon signed rank test) was performed. The effect of treatment allocation on the clinical secondary end points was assessed using Cox proportional hazards regression analysis.

Results
Patient Population

A patient enrollment flow diagram is presented in Figure 1. Baseline characteristics, as well as culprit vessel distribution, multivessel (≥2) disease, and thrombolysis in myocardial infarction flow after PPCI, are presented in the Table. All patients underwent emergency angiography. The chewing group and the standard group had a similar mean (SD) door-to-balloon time of 49 (47) vs 47 (23) minutes, respectively (95% CI, −24.96 to 21.25; P = .48), as well as infarct size as represented by mean (SD) left ventricular ejection fraction of 45% (12) vs 46% (13), respectively (95% CI, −8.06 to 5.90; P = .38).

Platelet Reactivity

Mean (SD) P2Y12 reaction units in the chewing group compared with the standard group at baseline, 30 minutes, 1 hour, and 4 hours after ticagrelor LD were 224 (33) vs 219 (44) (95% CI, −16.77 to 27.73; P = .26), 168 (78) vs 230 (69) (95% CI, −103.77 to −19.75; P = .003), 106 (90) vs 181 (89) (95% CI, −125.15 to −26.29; P = .005), and 43 (41) vs 51 (61) (95% CI, −36.34 to 21.14; P = .30), respectively. Platelet reactivity in the chewing group was significantly reduced by 24% at 30 minutes after ticagrelor LD (95% CI, 19.75 to 103.99; P = .001). The relative IPA in the chewing vs the standard group was 51% vs 10% (95% CI, 13.69 to 67.67; P = .005) at 1 hour and 81% vs 76% (95% CI, −12.32 to 16.79; P = .24) at 4 hours, respectively (Figure 2). Rates of HPR were markedly reduced in the chewing group compared with the standard group (eFigure in Supplement 2). Moreover, HPR was present in approximately half of the standard group at 1 hour.

Follow-up at 30 Days

The rate of major adverse cardiac and cerebrovascular events at 30 days was low, occurring in 1 patient in the chewing group (cardiogenic shock after percutaneous coronary intervention) and 1 patient in the standard group (recurrent acute coronary syndrome). None of the patients died during the study follow-up period. The chewing group and the standard group had similar adverse effect rates (6 [24%] vs 3 [12%]; 95% CI, 0.09-1.96; P = .46).

Discussion

To our knowledge, this is the first investigation to show that, in patients with STEMI undergoing PPCI, chewing an LD of ticagrelor, 180 mg, was associated with enhanced platelet inhibitory effects compared with standard ticagrelor administration, particularly in the early hours after drug administration. Notably, reduced platelet reactivity with chewing ticagrelor was observed as early as 30 minutes after drug administration. Accordingly, chewing ticagrelor led to a significant reduction in HPR rates, particularly at 1 hour after LD. In patients with STEMI and particularly in patients undergoing PPCI, the delayed onset of action to oral P2Y12 receptor inhibitors can last for several hours and cause an increased risk of thrombotic complications during and after PPCI.9,10 Results of our trial suggest that chewing ticagrelor offers either a faster absorption via the mucosa and/or a faster absorption in the stomach. The use of morphine has also been associated with a further delay in drug and thienopyridine absorption.11 Chewing ticagrelor could overcome the disadvantages of drug absorption via the gastrointestinal tract particularly during the first crucial hours of STEMI.

Limitations and Clinical Implications

Our study lacks pharmacokinetic confirmation, and therefore the results should be interpreted with caution. Although platelet reactivity has been associated with ischemic outcomes,12,13 it must be acknowledged that it is a surrogate outcome. Indeed, our single-center study included a relatively small sample size and therefore was not powered to assess clinical outcomes

Conclusions

Chewing an LD of ticagrelor, 180 mg, in patients with STEMI is feasible and facilitates a faster and more pronounced early IPA compared with a standard oral LD. Larger studies are warranted to investigate if our pharmacodynamics findings translate into improved clinical outcomes in patients with STEMI.

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Article Information

Accepted for Publication: September 4, 2017.

Corresponding Author: Elad Asher, MD, MHA, Heart Institute, Sheba Medical Center, Tel Hashomer 5265601, Israel (el.asher@gmail.com).

Author Contributions: Dr Asher had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Published Online: October 25, 2017. doi:10.1001/jamacardio.2017.3868

Study concept and design: Asher, Mazin, Guetta, Segev, Elian, Barbash, Beigel, Matetzky.

Acquisition, analysis, or interpretation of data: Tal, Mazin, Abu-Much, Sabbag, Katz, Regev, Chernomordik, Segev, Fefer, Narodistky, Beigel, Matetzky.

Drafting of the manuscript: Asher, Tal, Mazin, Abu-Much, Segev, Barbash, Matetzky.

Critical revision of the manuscript for important intellectual content: Sabbag, Katz, Regev, Chernomordik, Guetta, Segev, Elian, Barbash, Fefer, Narodistky, Beigel, Matetzky.

Statistical analysis: Sabbag, Regev, Barbash, Narodistky.

Obtained funding: Asher.

Administrative, technical, or material support: Tal, Mazin, Abu-Much, Sabbag, Katz, Chernomordik, Guetta, Elian, Barbash, Fefer, Beigel.

Study supervision: Asher, Segev, Barbash, Narodistky, Beigel, Matetzky.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was supported by the unrestricted Gassner Fund for Medical Research Grant.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the Platelets and Thrombosis in Sheba study group.

References
1.
Butler  K, Teng  R.  Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers.  Br J Clin Pharmacol. 2010;70(1):65-77.PubMedGoogle ScholarCrossref
2.
Birkeland  K, Parra  D, Rosenstein  R.  Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor.  J Blood Med. 2010;1:197-219.PubMedGoogle Scholar
3.
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(15):1601-1606.PubMedGoogle ScholarCrossref
4.
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.  JACC Cardiovasc Interv. 2015;8(11):1457-1467.PubMedGoogle ScholarCrossref
5.
Parodi  G, Xanthopoulou  I, Bellandi  B,  et al.  Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study.  J Am Coll Cardiol. 2015;65(5):511-512.PubMedGoogle ScholarCrossref
6.
Asher  E, Frydman  S, Katz  M,  et al; For The PLATIS (Platelets and Thrombosis in Sheba) Study Group.  Chewing vs swallowing ticagrelor to accelerate platelet inhibition in acute coronary syndrome: the CHEERS study.  Thromb Haemost. 2017;117(4):727-733.PubMedGoogle ScholarCrossref
7.
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.  JACC Cardiovasc Interv. 2010;3(1):35-40.PubMedGoogle ScholarCrossref
8.
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(10):1132-1137.PubMedGoogle ScholarCrossref
9.
Bhatt  DL, Stone  GW, Mahaffey  KW,  et al; CHAMPION PHOENIX Investigators.  Effect of platelet inhibition with cangrelor during PCI on ischemic events.  N Engl J Med. 2013;368(14):1303-1313.PubMedGoogle ScholarCrossref
10.
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(9909):1981-1992.PubMedGoogle ScholarCrossref
11.
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(7):630-635.PubMedGoogle ScholarCrossref
12.
Mascelli  MA, Kleiman  NS, Marciniak  SJ  Jr, Damaraju  L, Weisman  HF, Jordan  RE.  Therapeutic heparin concentrations augment platelet reactivity: implications for the pharmacologic assessment of the glycoprotein IIb/IIIa antagonist abciximab.  Am Heart J. 2000;139(4):696-703.PubMedGoogle ScholarCrossref
13.
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-I20.PubMedGoogle ScholarCrossref
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