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Figure 1.
Flow of Patients in TREAT Trial
Flow of Patients in TREAT Trial

For most included patients, randomized treatment did not begin immediately but rather hours after initiation of fibrinolytic therapy. In this sense, patients randomized to ticagrelor received the first dose of ticagrelor several hours after initiation of fibrinolytic therapy (median, 11.4 hours), and 90% were pretreated with clopidogrel.

Figure 2.
Major Bleeding (Thrombolysis in Myocardial Infarction [TIMI], Platelet Inhibition and Patient Outcomes [PLATO], and Bleeding Academic Research Consortium [BARC] Definitions) at 30 Days
Major Bleeding (Thrombolysis in Myocardial Infarction [TIMI], Platelet Inhibition and Patient Outcomes [PLATO], and Bleeding Academic Research Consortium [BARC] Definitions) at 30 Days

Difference (in percentage) presented as bilateral 95% confidence interval. 1% Absolute difference margin noninferiority test. Noninferiority test was done considering a 1-sided test.

Table 1.  
Characteristics of the Patients at Baseline
Characteristics of the Patients at Baseline
Table 2.  
Other Bleeding
Other Bleeding
Table 3.  
Efficacy Events Until 30 Days
Efficacy Events Until 30 Days
1.
O’Gara  PT, Kushner  FG, Ascheim  DD,  et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  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.  Circulation. 2013;127(4):e362-e425.PubMedGoogle ScholarCrossref
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Ibanez  B, James  S, Agewall  S,  et al; ESC Scientific Document Group.  2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).  Eur Heart J. 2018;39(2):119-177.PubMedGoogle ScholarCrossref
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Vora  AN, Holmes  DN, Rokos  I,  et al.  Fibrinolysis use among patients requiring interhospital transfer for ST-segment elevation myocardial infarction care: a report from the US National Cardiovascular Data Registry.  JAMA Intern Med. 2015;175(2):207-215.PubMedGoogle ScholarCrossref
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Gandhi  S, Zile  B, Tan  MK,  et al; Canadian ACS Reflective Group.  Increased uptake of guideline-recommended oral antiplatelet therapy: insights from the Canadian acute coronary syndrome reflective.  Can J Cardiol. 2014;30(12):1725-1731.PubMedGoogle ScholarCrossref
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Chen  ZM, Jiang  LX, Chen  YP,  et al; COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.  Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.  Lancet. 2005;366(9497):1607-1621.PubMedGoogle ScholarCrossref
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Sabatine  MS, Cannon  CP, Gibson  CM,  et al; CLARITY-TIMI 28 Investigators.  Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.  N Engl J Med. 2005;352(12):1179-1189.PubMedGoogle ScholarCrossref
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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(9):1038-1047.PubMedGoogle ScholarCrossref
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Husted  S, van Giezen  JJJ.  Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist.  Cardiovasc Ther. 2009;27(4):259-274.PubMedGoogle ScholarCrossref
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Wallentin  L, Becker  RC, Budaj  A,  et al; PLATO Investigators.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2009;361(11):1045-1057.PubMedGoogle ScholarCrossref
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Berwanger  O, Nicolau  JC, Carvalho  AC,  et al.  Ticagrelor versus Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction: Rationale and Design of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial.  Am Heart J. 2018.Google Scholar
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Steg  PG, James  S, Harrington  RA,  et al; PLATO Study Group.  Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis.  Circulation. 2010;122(21):2131-2141.PubMedGoogle ScholarCrossref
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Mehran  R, Rao  SV, Bhatt  DL,  et al.  Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.  Circulation. 2011;123(23):2736-2747.PubMedGoogle ScholarCrossref
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Montalescot  G, van ’t Hof  AW, Lapostolle  F,  et al; ATLANTIC Investigators.  Prehospital ticagrelor in ST-segment elevation myocardial infarction.  N Engl J Med. 2014;371(11):1016-1027.PubMedGoogle ScholarCrossref
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Van De Werf  F, Adgey  J, Ardissino  D,  et al; Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators.  Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.  Lancet. 1999;354(9180):716-722.PubMedGoogle ScholarCrossref
15.
Stone  GW, Witzenbichler  B, Guagliumi  G,  et al; HORIZONS-AMI Trial Investigators.  Bivalirudin during primary PCI in acute myocardial infarction.  N Engl J Med. 2008;358(21):2218-2230.PubMedGoogle ScholarCrossref
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R Core Team. R: A language and environment for statistical computing. http://www.R-project.org/. Published 2017. Accessed January 1, 2018.
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Dehghani  P, Lavoie  A, Lavi  S,  et al.  Effects of ticagrelor versus clopidogrel on platelet function in fibrinolytic-treated STEMI patients undergoing early PCI.  Am Heart J. 2017;192:105-112.PubMedGoogle ScholarCrossref
18.
Guimarães  LFC, Généreux  P, Silveira  D,  et al.  P2Y12receptor inhibition with prasugrel and ticagrelor in STEMI patients after fibrinolytic therapy: Analysis from the SAMPA randomized trial.  Int J Cardiol. 2017;230:204-208.PubMedGoogle ScholarCrossref
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Alexopoulos  D, Perperis  A, Koniari  I,  et al.  Ticagrelor versus high dose clopidogrel in ST-segment elevation myocardial infarction patients with high platelet reactivity post fibrinolysis.  J Thromb Thrombolysis. 2015;40(3):261-267.PubMedGoogle ScholarCrossref
Original Investigation
May 2018

Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction: A Randomized Clinical Trial

Author Affiliations
  • 1Research Institute, Heart Hospital, São Paulo, Brazil
  • 2Instituto do Coração, Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
  • 3Universidade Federal de São Paulo, São Paulo, Brazil
  • 4Fuwai Hospital, Beijing, China
  • 5Canadian Heart Research Centre, Toronto, Canada
  • 6South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia
  • 7Institute of Cardiology, Emergency Cardiology Department, Kiev, Ukraine
  • 8Pirogov Russian National Research Medical University, Moscow, Russia
  • 9Hospital de Alta Complejidad El Cruce, Buenos Aires, Argentina
  • 10Universidad Peruana Cayetano Heredia, Lima, Peru
  • 11Hospital e Maternidade Celso Pierro, Campinas, Brazil
  • 12Hospital Geral do Grajaú, São Paulo, Brazil
  • 13Heart Hospital, São Paulo, Brazil
  • 14Duke University Medical Center, Durham, North Carolina
  • 15Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand
JAMA Cardiol. 2018;3(5):391-399. doi:10.1001/jamacardio.2018.0612
Key Points

Question  In patients with ST-elevation myocardial infarction treated with fibrinolytic therapy, is ticagrelor noninferior to clopidogrel with respect to thrombolysis in myocardial infarction major bleeding at 30 days?

Findings  In this randomized clinical trial of 3799 patients, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for thrombolysis in myocardial infarction major bleeding at 30 days. However, minor bleeding was increased with ticagrelor and there was no benefit on efficacy outcomes.

Meaning  Because most of the included patients were pretreated with clopidogrel, these findings reflect mostly the noninferiority of switching from clopidogrel to ticagrelor in patients already fully loaded with clopidogrel.

Abstract

Importance  The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain.

Objective  To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy.

Design, Setting and Participants  We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%.

Interventions  Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel.

Main Outcomes and Measures  The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days.

Results  The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, −0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, −0.18%; 95% CI, −0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57).

Conclusions and Relevance  In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days.

Trial Registration  clinicaltrials.gov Identifier: NCT02298088

Introduction

Primary percutaneous coronary intervention (PCI) represents the preferred reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI).1,2 However, it is not possible for patients to be treated at hospitals with PCI capabilities in a timely manner as directed by clinical practice guidelines in many parts of the world.3,4 As a result, many patients with STEMI receive fibrinolytic therapy as the initial reperfusion strategy.1-4 Two large-scale randomized trials5,6 have established that dual antiplatelet therapy with aspirin and clopidogrel reduces major cardiovascular events in fibrinolytic-treated patients with STEMI.

Ticagrelor, a reversible and direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12,7,8 provides faster, greater, and more consistent P2Y12 inhibition than clopidogrel. In the Platelet Inhibition and Patient Outcomes (PLATO) study,9 treatment with ticagrelor compared with clopidogrel significantly reduced the rate of death from vascular causes, MI, or stroke without an increase in the rate of overall major bleeding.

Despite these benefits, patients who received fibrinolytic therapy in the preceding 24 hours were excluded. Accordingly, to our knowledge, large-scale randomized trials evaluating the safety and efficacy of ticagrelor in this population have not been performed. The main concern regarding the use of ticagrelor in this scenario is related to the risk of major bleeding, especially intracranial or fatal bleeding. These patients with bleeding complications have greater rates of major adverse cardiovascular events and mortality. Thus, the Ticagrelor in Patients With ST-Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis (TREAT) trial was conducted to evaluate the safety of ticagrelor in this clinical setting.

Methods
Study Design Oversight

The trial protocol is available in Supplement 1 and the statistical analysis plan is available in Supplement 2. Briefly, the TREAT trial10 was an academically led, phase 3, international, multicenter, randomized, and open-label study with blinded outcome assessment that involved 10 countries (Argentina, Australia, Brazil, Canada, China, Colombia, New Zealand, Peru, Russia, and Ukraine). The steering committee, consisting exclusively of academic members, designed and oversaw the conduct of the trial. An independent data monitoring committee monitored the trial and had access to the unblinded data. Site management, data management, and analysis were performed by the Research Institute–Heart Hospital, São Paulo, Brazil. The study design was approved by the appropriate national and institutional regulatory authorities and ethics committees, and all participants provided written informed consent.

Patients

Patients were eligible for enrollment if they presented within 24 hours after the onset of symptoms, had evidence of acute ST-elevation on their qualifying electrocardiogram (at least 2 should be 1 mm in 2 contiguous peripheral or precordial leads in men and 1.5-mm elevation in V1-V3 in women and 1-mm in limb leads), were younger than 75 years, and received fibrinolytic therapy. Key exclusion criteria were any contraindication to the use of clopidogrel, use of oral anticoagulation therapy, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer. The complete list of inclusion and exclusion criteria is provided in eMethods 1 of Supplement 3. Because patients who received fibrinolytic therapy in the previous 24 hours were excluded from the PLATO trial, we decided to include patients within 24 hours of symptom onset to fill the literature gap. Moreover, in an informal survey conducted with some potential sites before trial start, it was considered that establishing a very narrow window from fibrinolytic therapy to randomization would make recruitment very challenging. That approach would demand that the trial be conducted in small regional hospitals or mobile units, where the research infrastructure and expertise is very limited in most of the participating countries.

Randomization and Study Treatment

Patients were randomly assigned, in a 1 to 1 ratio, to receive ticagrelor with a loading dose of 180 mg or clopidogrel (with a loading dose of 300 to 600 mg) as early as possible after the index event and not more than 24 hours after the event. Randomization was performed in a concealed fashion with the use of an automated web-based system, in permuted blocks of 4, stratified according to site. Patients pretreated with clopidogrel before randomization were still eligible. If randomized to ticagrelor, the trial loading dose was recommended, and if randomized to clopidogrel, the patients could receive an additional 300 mg of clopidogrel at the discretion of the investigator and in accordance to local guidelines if undergoing PCI. The randomized maintenance therapy for ticagrelor was 90 mg twice daily and for clopidogrel was 75 mg once daily.

All patients received acetylsalicylic acid (ASA), 75 to 100 mg daily, during all the follow-up unless intolerant. For patients not previously receiving ASA, a loading dose of 162 mg to 325 mg was recommended. Investigators were encouraged to practice evidence-based medicine and follow appropriate guidelines1,2 in the other aspects of treating STEMI; decisions about the use of other treatments for acute MI and subsequent revascularization procedures were left to the discretion of the treating physicians.

Clinical Outcomes

The primary safety outcome was major bleeding, according to the Thrombolysis in Myocardial Infarction (TIMI) definition. Secondary safety outcomes include major or minor bleeding according to the PLATO trial9,11 and the Bleeding Academic Research Consortium (BARC)12 definitions and clinically relevant nonmajor bleeding or minor bleeding according to the TIMI definition.

Exploratory secondary efficacy outcomes included the composite outcome of death from vascular causes, MI, or stroke (similar to the PLATO primary outcome), and the same composite outcome with the addition of recurrent ischemia, transient ischemic attack, or other arterial thrombotic events. We evaluated individual components of the composite efficacy outcomes and all-cause mortality at 30 days.

The primary and secondary outcomes were adjudicated with the use of prespecified criteria by an independent clinical events committee whose members were unaware of the group assignments. Detailed definitions of outcomes are provided in eMethods 2 of Supplement 3.

Statistical Analysis

Concerns around major bleeding events were the main driver for the choice of the primary outcome of TREAT trial and for the noninferiority design. When TREAT was being designed, to our knowledge, there were no reported trials of ticagrelor in fibrinolytic-treated patients with STEMI that could inform major bleeding rates. Thus, we based our sample size on previous trials of ticagrelor in patients with STEMI undergoing PCI.13 In this regard, TIMI major bleeding rates at 30 days were projected to be around 1.2%. We considered an increase of bleeding of less than 1.0% to fulfill clinical criteria of noninferiority, which reflects what others have used as evidence of noninferiority regarding safety and efficacy outcomes, including major bleeding and mortality, in patients with acute coronary syndromes.14,15 We required a sample size of at least 1897 patients per group to provide greater than 90% statistical power, considering a noninferiority (absolute) margin of 1.0%, a 1-sided α of 2.5%, and assuming a 1 to 1 allocation ratio.

Continuous variables are reported as mean and standard deviation, or medians and interquartile range (IQR) as appropriate. Categorical variables are summarized as frequencies.

All patients who had been randomized to a treatment group were included in the intention-to-treat analyses. We also conducted sensitivity analyses in the per protocol population as prespecified in our statistical analysis plan (Supplement 2). Bleeding events were compared between groups based on the normal approximation to the binomial distribution. Efficacy outcomes were analyzed with the use of a Cox proportional hazards model. The point estimate and 2-sided 95% confidence intervals for the hazard ratio were calculated for each outcome. Prespecified safety and efficacy analyses were performed in subgroups according to age, sex, Killip risk score, diabetes mellitus, time from start of index event to randomization, aspirin, treatment with fibrin-specific or nonfibrin-specific fibrinolytics, and use of clopidogrel before randomization. The rates of bleeding and efficacy events are reported as percentages. All reported P values for noninferiority are 1-sided, and reported P values for superiority are 2-sided. All analyses were performed with the use of R (R Programming).16

Results
Study Patients and Study Drugs

We recruited 3799 patients from 152 centers in 10 countries from November 2015 through November 2017. The follow-up period for the 30-day data ended in December 2017, when information on vital status was available for all patients except 8 (Figure 1). Table 1 presents the baseline characteristics. The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, 1759 of 3799 patients (46.3%) were current smokers, and 328 of 3799 patients (8.6%) had a history of MI. A total of 3795 of 3799 (99.9%) of the patients received fibrinolytic agent, of whom 2881 of 3799 (75.9%) received a fibrin-specific agent. The 2 treatment groups were well balanced as demonstrated by the baseline characteristics (Table 1) and the nonstudy medications and procedures (eTable 1 in Supplement 3). Both groups were randomized with a median of 2.6 hours (IQR, 1.5-4.3 hours) from chest pain to fibrinolytic therapy and had a median of 11.4 hours (IQR, 5.8-18.2 hours) after fibrinolytic therapy to randomization. In both groups, 3376 of 3774 patients (89.4%) received clopidogrel prior to randomization, usually at the 300-mg dose. A total of 3755 of 3799 patients (98.8%) received aspirin. The overall rate of adherence to the study drug at 30 days was 90.3%, as assessed by the site investigators.

Bleeding

The primary outcome (TIMI major bleeding up to 30 days) occurred in 14 of 1913 patients (0.73%) in the ticagrelor group and 13 of 1886 patients (0.69%) in the clopidogrel group (absolute difference, 0.04%; 95% CI, −0.49% to 0.58%; P < .001 for noninferiority) (Figure 2; eFigure 1 in Supplement 3). Results were similar for the per protocol and other sensitivity analyses (eTable2 in Supplement 3). Major bleeding as assessed by the PLATO criteria and BARC types 3 to 5 bleeding occurred in 23 of 1913 patients (1.20%) in the ticagrelor group and in 26 of 1886 patients (1.38%) in the clopidogrel group (absolute difference, −0.18%; 95% CI, −0.89% to 0.54%; P = .001 for noninferiority) (Figure 2; eFigures 2 and 3 in Supplement 3).

The rates of fatal bleeding (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and the clopidogrel groups, respectively. Minor and minimal bleeding, as well as total bleeding, were more common with ticagrelor than with clopidogrel, irrespective of the classification used (Table 2).

In patients who received study drugs within 4 hours after initiation of fibrinolytic therapy, the TIMI major bleeding events rates were 1.53% and 1.22% for the ticagrelor and clopidogrel groups, respectively (P = .73). Among these patients, there were also no statistically significant differences between ticagrelor and clopidogrel with respect to PLATO major bleeding and BARC types 3 to 5 bleeding rates (eFigure 4 in Supplement 3).

Efficacy

The exploratory secondary efficacy outcomes and interventions up to 30 days are shown in Table 3. The composite outcome of death from vascular causes, MI, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57). The rates of individual outcomes of MI, stroke, and other arterial thrombotic events were similar in the ticagrelor and clopidogrel groups.

Other Adverse Events

Discontinuation of the study drug owing to serious adverse events was similar between ticagrelor and clopidogrel groups (0.40% vs 0.40%; P = .99). Dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 265 of 1913 patients [13.9%] vs 144 of 1886 patients [7.6%], respectively) (eTable 3 in Supplement 3). Few patients discontinued the study drug because of dyspnea (19 of 1913 patients [1.0%] in the ticagrelor group and none in the clopidogrel group). The frequencies of serious adverse events were similar between groups.

Subgroup Analysis

The treatment effects of ticagrelor vs clopidogrel for the primary safety outcome and for the exploratory efficacy outcome were consistent among all subgroups (eTables 4 and 5 in Supplement 3).

Discussion

In this trial of patients younger than 75 years with STEMI who received fibrinolytic therapy as their initial reperfusion strategy,1,2 delayed administration of ticagrelor was noninferior to clopidogrel with respect to major bleeding (according to the TIMI, PLATO, and BARC classifications) at 30 days. Results were consistent between the intention-to-treat and per protocol analyses. Importantly, the rates of fatal and intracranial bleeding were also similar between the ticagrelor and clopidogrel groups. In contrast, the rates of minor, minimal, and total bleeding events were numerically higher with ticagrelor than with clopidogrel. Because most of the included patients were pretreated with clopidogrel, these findings reflect mostly the noninferiority of switching from clopidogrel to ticagrelor in patients already treated with clopidogrel.

Our findings are also consistent with previous smaller trials comparing ticagrelor and clopidogrel in patients with STEMI treated with fibrinolytics. A trial by Dehghani et al17 compared ticagrelor with clopidogrel in 144 patients undergoing early PCI post-reperfusion with tenectaplase. All patients received clopidogrel prerandomization, and the median time of thrombolytic administration to randomization (and initiation of ticagrelor vs clopidogrel) was about 6 hours. The BARC types 3 to 5 bleeding rates at 30 days were 1.3% in both the ticagrelor and clopidogrel groups at 30 days, which are similar to the rates observed in TREAT for the same outcome. The Sampling P2Y12 Receptor Inhibition With Prasugrel and Ticagrelor in Patients Submitted to Thrombolysis (SAMPA)18 trial compared ticagrelor and prasugrel in patients with STEMI post-fibrinolytic therapy. Similar to TREAT, all patients also received clopidogrel prerandomization, and the median time to randomization after thrombolytic therapy was 12.2 hours. No major bleeding events were observed within 30 days. Another small trial also found low bleeding rates in patients receiving ticagrelor after fibrinolytic therapy.19

Factors that could be related to the low major bleeding rates observed in our trial include the exclusion of patients older than 75 years, the predominantly male population, and the relative low risk of included patients. In addition, despite the fact that we used a very detailed and standardized adjudication process, lower transfusion rates in some participating countries could have decreased ascertainment of major bleeding events. Nevertheless, the major bleeding rates found in TREAT are similar to what was seen in the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)5 trial, in which rates of fatal, transfused, or intracranial bleeds together in fibrinolytic-treated patients who received clopidogrel were 0.65%.

Limitations

Comparisons of safety event rates between TREAT and other large-scale ticagrelor trials in patients with acute coronary syndromes are limited owing to differences in study designs, populations, and follow-up. Nevertheless, in the PLATO STEMI11 analysis, intracranial bleeding was very rare and not different between both groups (0.4% vs 0.2% in the ticagrelor and clopidogrel groups, respectively). This finding is similar to the rates observed in our trial. Given the observed low major bleeding rates, another important limitation of our trial is that one might consider our noninferiority margin of 1% to be quite wide and reflective of the modest sample size. This margin was chosen based on expert opinion and is similar to the margins used by previous acute coronary syndromes trials,14,15 although trials in populations similar to TREAT were not available at the time the protocol was designed. On the other hand, the upper boundaries of the confidence intervals for major bleeding according to different classifications were all lower than 0.6; thus, far from the 1% prespecified margin. Finally, as in previous ticagrelor trials, despite the fact that dyspnea was more common in patients receiving ticagrelor than clopidogrel, discontinuation owing to this adverse event was uncommon in the TREAT trial.

In our trial, rates of major cardiovascular events were similar between ticagrelor and clopidogrel at 30 days. Owing to the low number of events, our statistical power to assess superiority is limited; thus, these findings must be interpreted as exploratory. The lack of short-term differences between ticagrelor and clopidogrel is consistent with previous trials. In the PLATO STEMI11 analysis (n = 7544), the effects on major cardiovascular events appeared to accrue over time, and the event curves suggested that the bulk of the clinical benefit was obtained during long-term treatment. Additionally, our results might have been influenced, at least in part, by the stringent criteria that used by the clinical classification committee for outcomes, such as reinfarction, coupled with the challenge of adjudicating some of these outcomes in the setting of STEMI and rising biomarker levels.

The median time of thrombolytic administration to randomization, as is true for previous smaller studies, was about 11 hours, which is beyond the half-life of fibrin-specific fibrinolytics. Thus, it is likely that patients who had early bleeding events associated with fibrinolytic therapy were excluded. Nevertheless, in TREAT, we were still able to include patients within the first 4 hours of receiving fibrinolytic therapy. As expected, the TIMI major bleeding event rates at 30 days were higher (1.37% in both groups) in this subgroup compared with patients who were randomized later. Although our trial was not powered to determine noninferiority in specific subgroups, including patients who received ticagrelor soon after fibrinolytic therapy, major bleeding rates were numerically similar between groups irrespective of time from fibrinolytic therapy to randomization. Our trial does not address treatment of patients older than 75 years, who were excluded.

Most patients in our trial received clopidogrel prerandomization. In this regard, given that patients who received fibrinolytic therapy in the previous 24 hours were excluded from the PLATO trial and that STEMI guidelines2 recommend that ticagrelor should only be initiated after 48 hours after fibrinolysis, we believe that our trial adds new safety information to practicing physicians. Furthermore, approximately 50% of patients in the PLATO trial also received clopidogrel prior to randomization to either ticagrelor or clopidogrel and bleeding risk in these patients appeared to be comparable with those who had not received prior open-label clopidogrel. Based on our findings, patients with STEMI younger than 75 years who initially received clopidogrel can be safely switched to ticagrelor in the first 24 hours after fibrinolysis. Whether this strategy will result in fewer cardiovascular events in the long term remains to be determined. Our trial was an investigator-initiated trial with limited funding that did not allow a double-dummy design. We attempted to minimize the risk of bias associated with the open-label nature of the study by performing blinded outcome adjudication.

Conclusions

In patients younger than 75 years with STEMI, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days. However, minor bleeding was increased with ticagrelor, and there was no benefit on efficacy outcomes.

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Article Information

Corresponding Author: Otavio Berwanger, MD, PhD, Research Institute, Heart Hospital, Abílio Soares St 250, 12th Floor, 04005-000, São Paulo, SP, Brazil (otavioberwanger@gmail.com).

Accepted for Publication: February 23, 2018.

Correction: This article was corrected on May 16, 2018, to fix errors in the author byline.

Published Online: March 11, 2018. doi:10.1001/jamacardio.2018.0612

Author Contributions: Dr Berwanger 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.

Concept and design: Berwanger, Nicolau, Carvalho, Nicholls, Guimaraes, Damiani, Paisani, Lasagno, Candido, Valeis, Moia, White, Lopes.

Acquisition, analysis, or interpretation of data: Berwanger, Nicolau, Carvalho, Nicholls, Parkhomenko, Tajer, Malaga, de Luca, Gabriel Melo de Barros e Silva, Damiani, Paisani, Lasagno, Candido, White, Lopes.

Drafting of the manuscript: Berwanger, Malaga, de Luca, Guimaraes, Gabriel Melo de Barros e Silva, Damiani, Paisani, Lasagno, Candido, Valeis, Moia, Lopes.

Critical revision of the manuscript for important intellectual content: Berwanger, Nicolau, Carvalho, Nicholls, Parkhomenko, Tajer, Malaga, Guimaraes, Gabriel Melo de Barros e Silva, White, Lopes.

Statistical analysis: Tajer, Damiani.

Obtained funding: Berwanger, Nicolau.

Administrative, technical, or material support: Berwanger, Carvalho, Nicholls, Malaga, de Luca, Guimaraes, Paisani, Lasagno, Candido, Valeis, Moia, White.

Supervision: Berwanger, Nicolau, Parkhomenko, Tajer, Gabriel Melo de Barros e Silva, Moia, Lopes.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Berwanger reports grants from AstraZeneca, Amgen, Bayer, Novo Nordisk, Boehringer Ingelheim, and Roche Diagnosis; personal fees from AstraZeneca, Bayer, Roche Diagnosis, and Sanofi. Dr Damiani reports grants from AstraZeneca. Dr De Luca reports grants from AstraZeneca, Boehringer Ingelheim, Bayer, and Daiichi Sankyo. Dr Gabriel Melo de Barros e Silva reports personal fees from Daiichi Sankyo and Boehringer Ingelheim. Dr Goodman reports grants for the current work from Research Institute, Heart Hospital; grants from AstraZeneca, Lilly, and Sanofi outside the submitted work; and personal fees from AstraZeneca, Lilly, and Sanofi outside the submitted work. Dr Lopes reports grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer and personal fees from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. Dr Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, the Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience and personal fees from AstraZeneca, Anthera, Eli Lilly, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr Nicolau reports grants from AstraZeneca and personal fees from Sanofi. Dr Parkhomenko reports grants and personal fees from Pfizer, Bayer, Janssen, Sanofi-Aventis, MSD, and AstraZeneca. Dr Saraiva reports personal fees for the current work from AstraZeneca, Boehringer, Janssen, Pfizer, Bristol-Myers Squibb, Novartis, Amgen, Sanofi, and Merck Sharp and Dohme and personal fees from AstraZeneca, Boehringer, Pfizer, and Novartis outside the submitted work. Dr White reports personal fees from AstraZeneca for the current work; grants from Eli Lilly and the National Institutes of Health outside the submitted work, and personal fees from Eli Lilly and Omthera Pharmaceuticals outside the submitted work. No other disclosures were reported.

Funding/Support: The TREAT trial was an investigator-initiated trial funded by AstraZeneca.

Role of the Funder/Sponsor: The funding source 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.

Group Information: The TREAT Study Group members are made up of the following:

Independent Data Monitoring Committee: John H. Alexander, MD, PhD (chair): DMC voting members: Karen Pieper, PhD; Stefan James, MD, PhD; DMC statistician: Tiago Mendonça, Stat.

Clinical Events Committee: Renato D. Lopes, MD, MHS, PhD (chair); CEC reviewers: Pedro G. M. de Barros e Silva, MD, MHS, PhD; Helio P. Guimaraes, MD, PhD; Maria Julia M. Carrion, MD, PhD; Leticia K. Dourado, MD, PhD; Jiamin Liu, MD; Haibo Zhang, MD; Wuhan Bilige, MD; Yaroslav Lutay, MD; Oleg Irkin MD; CEC staff: Diogo D. F. Moia, PharmD; Carolina T. Candido, PharmD; Camila M. R. Lasagno, BSc.

International Study Coordinating Office: Research Institute–Heart Hospital, São Paulo, Brazil: Otavio Berwanger (chair), MD, PhD; Helio P. Guimaraes, MD, PhD; Pedro G. M. de Barros e Silva, MD, MHS, PhD; Diogo D. F. Moia, PharmD; Camila M. R. Lasagno, BSc; Carolina T. Candido, PharmD; Denise M. Paisani, PhD; Nanci Valeis, Dr; Beatriz G. Pacheco, PharmD; Lucas P. Damiani, MSc; Renato H. N. Santos, Stat; Alessandra Kodama, BSc; Bruna Sampaio, BSc.

Regional Study Coordinating Office: South Australian Health and Medical Research Institute, Adelaide, Australia: Liddy Griffith (project manager), Juanita Ottaway, Christine Edwards, Deirdre Murphy; Canadian Heart Research Centre, Toronto, Ontario, Canada: Caroline Spindler (project manager), Diane Camara; Oxford Centre for International Health Research–Fuwai Hospital, Beijing, China: Hao Yang (project manager), Li Li, Jinwang Song, Siyuan Kong, Runjia Zheng, Jia Li, Wenjuan Wang, Xiaoqian Shan, Kaiqi Shang; Green Lane Coordinating Centre Ltd, Auckland, New Zealand: Caroline Alsweiler (project manager), Darshana Karelia; Universidad Peruana Cayetano Heredia, Lima, Peru: Elsa Rosa Neira Sánchez (project manager); ALMEDIS, Moscow, Russia: Alexandra Kovelenova (project manager), Elena Kobazeva, Olga Karnishina; Regional Research Coordinating Ukraine, Kiev, Ukraine: Lyudmyla Parkhomenko (project manager).

Site Investigators

Argentina: Hospital El Cruce Nestor Kirschner: Maximiliano De Abreu; Hospital Zenón Santillan: Gustavo Paterlini; Hospital Interzonal General de Agudos Dr José Penna: Nadia Budasi; Idytac- Hospital Español de La Plata: Pablo Pollono; Hospital Alvarez: Daniel Avayu; Sanatorio Modelo de Quilmes: Alberto Fernandez.

Australia: Royal Adelaide Hospital: Stephen Nicholls; Wollongong Hospital: Astin Lee; Liverpool Hospital: John French; John Hunter Hospital: Nicholas Collins; Flinders Medical Centre: Derek Chew; Cairns Hospital: Gregory Starmer; Townsville Hospital: Ryan Schrale; Mildura Base Hospital: Alan Soward; Fiona Stanley Hospital: Whelan; The Alfred Hospital: James Shaw.

Brazil: Universidade Federal de São Paulo: Antonio Carlos Carvalho; Hospital Geral do Grajaú/UNISA: Fábio Augusto de Luca; Hospital Municipal de Emergência Albert Sabin: Karina Margareth Kuniyoshi; Hospital Universitário São José: Bruno Ramos Nascimento; Hospital das Clínicas–UFMG: Luísa Campos Caldeira Brant; Hospital Municipal do Campo Limpo: Vinicius Garcia de Vitro; Hospital Pronto Socorro e Maternidade Santa Lucia: Ricardo Reinaldo Bergo; Santa Casa de Belo Horizonte: Ricardo Wang; Hospital TotalCor: Thiago Andrade de Macêdo; Prevent Senior: Rodrigo Barbosa Esper; Cardiolima: Carlos Eduardo Batista de Lima; Hospital e Maternidade Celso Pierro: Jose Francisco Kerr Saraiva; Hospital Agamenon Magalhães: João Batista de Moura Xavier de Moraes Junior; Hospital e Pronto-Socorro 28 de Agosto: Wilson de Oliveira Filho; Santa Casa de São José do Rio Preto: Monica Buchala; Hospital de Base do Distrito Federal: Jose Carlos Quinaglia e Silva; Hospital Lifecenter: Estevão Lanna Figueiredo; Hospital e Clínica São Roque: Ricardo D'Oliveira Vieira; Centro de Pesquisa Clínica da FUC-ICFUC: Alexandre Schaan de Quadros; Santa Casa de Montes Claros: Daniel Silva Ramos; Hospital do Mandaqui: Ana Karolina Barreto Berselli Marinho; Hospital de Clinicas da Universidade Estadual de Campinas: Andrei Sposito; Hospital de Messejana: Frederico Augusto de Silva e Lima; Instituto de Cardiologia do Distrito Federal: Luciano de Moura Santos; Hospital São Vicente de Paulo: Rogério Tadeu Tumelero.

Canada: Royal Alexandra Hospital: Neil Brass; Southlake Regional Health Centre–Interventional Cardiology: Warren Cantor; Regina General Hospital–Prairie Vascular Research Network–SETFAST Coordinating Centre: Payam Dehghani; New Brunswick Heart Centre Research Initiative: Sohrab Lutchmedial; University Hospital/London Health Sciences Centre - Interventional Cardiology: Shahar Lavi; St Boniface General Hospital: Basam Elbarouni; Victoria Heart Institute Foundation: Imad Nadra; University of Alberta Hospital: Robert Welsh; Centre Intégré Universitaire de Santé et de Services Sociaux de la Mauricie-et-du-Centre-du-Québec: Ricardo Costa; St Mary's General Hospital: Jaffer Sayed; Queen Elizabeth II Health Sciences Centre: Tony Lee; Inst Uni de Cardiologie et Pneumologie de Quebec: Jean Pierre Dery; Peterborough Regional Health Centre: Warren Ball; Thunder Bay Regional Health Sciences Centre - Cardiac Cath Lab: Mark Henderson; University of Ottawa Heart Institute: Michel Le May; Centre Hospitalier Universitaire de Sherbrooke: Benoit Daneault; Windsor Regional Hospital: Mark Kotowyc.

China: Dancheng County People’s Hospital: Yuwang Yang; Lingbao First People’s Hospital: Wanke Li; Qinyang People’s Hospital: Xiaowen Ma; Gongyi People’s Hospital: Tianmin Du; Wen Country People´s Hospital: Xiaoli Ji; Huaiyang County People’s Hospital: Tingchun Chen; Chaoyang Second People’s Hospital: Huixin Li; Yongcheng People’s Hospital: Changming Tian; Alxa League Central Hospital: Xiaoting Duan; Qi County People’s Hospital: Baoqin Gu; Urad Front Banner People’s Hospital: Lijuan Zhang; Hulunbuir People’s Hospital: Zhonghua Cui; Dongfeng County Hospital: Wei Liu; Laoting Hospital: Keyong Shang; Heze Municipal Hospital: Yong Wang; Ruyang People’s Hospital: Chengning Shen; Anhui Province Mengcheng County, People’s Hospital: Haiyan Yan; Houma People’s Hospital: Tingchun Chen; Zhangye People’s Hospital: Xia wang; Feng County People’s Hospita: Feng Wang; Shenyang Sujiatun District Central Hospital: Hang Che; Laixi People’s Hospital: Xu Jiang; Binzhou City Center Hospital: Lijun Meng; Jiang Hua Yao Autonomous County People’s Hospital: Fuxian Zhao; Hunchun People’s Hospital: Changhong Guo; Shenyang the Fourth Hospital of People: Yinjun Li; Third Affiliated Hospital of Inner Mongolia Medical University: Yongdong Li; Puyang Zhongyuan Oil field General Hospital: Hengliang Wang; Dengfeng People’s Hospital: Hongxu Geng; Changyuan County People’s Hospital: Guorui Hou; The First People’s Hospital of YueYang: Xiping Xu; The Second Hospital of Liaocheng: Yun Zhang ; Wuhai People’s Hospital: Zhaohai Zhou; Anshan Changda Hospital: Xiang Jin; Shangqiu Changzheng People’s Hospital: Qian Wang; Wuyishan Municipal Hospital: Lili Yan; Benxi Jinshan Hospital: Guoquan Xiu; The Third People’s Hospital of LiaoYang: Aili Huang; Xinmin People’s Hospital: Bo Jiang; Sanmenxia Central Hospital: Huiyu Wang; Dunhua Hospital: Fanju Meng; Affiliated PuAi Hospital of Tongji Medical College: Ye Gu; The First Hospital of Fangshan District, Beijing: Xuemei Peng; Wuchuan People’s Hospital: Xuelian Deng; Jingxing County Hospital: Zhenhai Zhao; Fushun Mining Bureau General Hospital: Zhi Dong; Qinghai Cardiovascular Hospital: Bo Chen.

Colombia: Foundation Cardiomet Cequin: Gregorio S. Vallejo; Centro de Diagnostico: Fernando M. Jattin.

New Zealand: Tauranga Hospital: Barry Kneale; Taranaki Hospital: Ian Ternouth; Nelson Hospital: Nick Fisher; Hawkes Bay Hospital: Miles Williams; Rotorua Hospital: Peace Tamuno; Whangarei Base Hopsital: Samraj Nandra; Thames Hospital: Vijaya Pera.

Peru: Clínica Internacional: Fanny Otiniano; Hospital Cayetano Heredia: Aida Rotta Rotta; Hospital Regional de Lambayeque: Ciro Davilla Díaz; Clínica San Pablo: Edith Chavez; Hospital Hipólito Unanue: Yudy Roldán Concha.

Russia: Regional State Budget Healthcare Institution Altai Regional Cardiology Dispensary: Duda Alexej Ivanovich; Federal State Budget Science Institution “Science and Research Institute of Cardiology”: Markov Valentin Alekseevich; State Healthcare Institution “Belgorod Regional Clinical Hospital named after Prelate Ioasaf: Konstantinov Sergey Leonidovich; State Budget Healthcare Institution Ryazan region Regional Clinical Hospital: Aksentev Sergej Bronislavovich; Tver Regional Clinical Hospital: V. V. Bobkov; State Budget Educational Institution of Higher Professional Education “Smolensk State Medical University” Ministry of Healthcare of Russian Federation, clinical facility is State Budget Healthcare Institution “Smolensk regional clinical hospital”: Milyagin Viktor Artemevich; State Regional Budget Healthcare Institution Murmansk region Clinical Hospital named after P.A. Bayandin: Klejn Garri Valterovich; State Budget Healthcare Institution Vladimir region City Hospital #4: Kulibaba Elena Viktorovna; State Budget Healthcare Institution of Yaroslavl region “Regional clinical hospital”: Khrustalev Oleg Anatolevich; Budget Healthcare Institution Voronezh region City Clinical Emergency Care Hospital #1: Karpov Jurij Borisovich; Municipal Healthcare Institution Lyubertsy regional Hospital #2: Ginzburg Moisej Lvovich; State Budget Healthcare Institution Leningrad region Gatchina Clinical Inter-district Hospital: Ermoshkina Lyudmila Grigorevna ; State Budget Healthcare Institution Chelyabinsk regional clinical hospital #3: Sokolova Nadezhda Ivanovna; State Healthcare Institution Irkutsk regional clinical hospital: Ovcharenko Elena Yakovlevna; Municipal Budget Healthcare Institution Rostov-on-Don City Emergency Care Hospital: Khaisheva Larisa Anatolevna; State Healthcare Institution of Tula Region “Tula regional clinical hospital: Gomova Tatiana Alexandrovna; Regional State Budget Healthcare Institution Krasnoyarsk Regional Clinical Hospital: Linyov Kirill Aleksandrovich; Kirov Regional State Budget Healthcare Institution Kirov City clinical hospital 1: Solovev Oleg Vladimirovich; State Budget Healthcare Institution Novosibirsk region City Clinical Hospital #34: Nikolaev Konstantin Yurevich; Institution of the Russian academy of Sciences Hospital of Pushchino Research Center of RAS: Suslikov Aleksandr Vladimirovich.

Ukraine: City Clinical Hospital 1: Igor Kovalskyy; Sumu regional Cardiology Dispensary: Igor Martsovenko; Municipal Healthcare Institution “Kharkiv City Clinical Hospital #8, Cardiology Department for MI patients N1, Kharkiv Medical Academy of Postgraduate Education, Chair of Cardiology and Functional Diagnostics: Vira Tseluyko; MI “Regional Medical Center of Cardiovascular Diseases” of Zaporizhzhia Regional Council, Intensive Care Unit: Yaroslav Malynovskyy; Cherkasy Regional Cardiology Center, Department of Acute Heart Failure and Arrythmia: Svitlana Zhurba; Kiev Oleksandrivsk Clinical Hospital, department of Cardiology Reanimation, National Medical University: Igor Prudkyy; MI Rivne Regional Clinical Hospital: Larysa Vereshchuk; Kyiv City Clinical Hospital 1, Department of Emergency Cardiology: Oleksandr Karpenko; Municipal Institution Central city clinical hospital N1, Cardiology Department for MI patients: Anatoliy Zavgorodniy; Ivano-Frankivsk Regional Clinical Cardiological Dispensary, Department of Anestesiology with Intensive Care Unit, Ivano-Frankivsk National Medical University, Chair of Internal Medicine 2: Igor Vakaliuk; National Institut of Therapy named after L.T. Malaya NAMS of Ukraine, Department of Acute Myocardial Infarction: Mykola Kopytsia; MI City Clinical Hospital N3, Department of Intensice Cardiology Care: Borys Goloborodko; Kyiv Emergency Care Hospital, Infarction Department: Leonid Rudenko.

Additonal Contributions: The trial was coordinated by the Research Institute–Heart Hospital, São Paulo, Brazil.

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