Full transparency of ticagrelor trials in coronary artery disease should be warranted

Figures & data

Table 1. Designs of the trials discussed within manuscript

TRIALS	POPULATION, MEAN AGE	INTERVENTION	COMPARATOR	MEAN or MEDIAN DURATION	PRIMARY OUTCOME	Results for the primary outcome
PLATO[4]	18,624 patients (62 years old) admitted to the hospital with an ACS	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter)	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter)	12 months	Death from vascular causes, MI, or stroke	At 12 months, the primary end point had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (HR 0.84; 95% CI 0.77 to 0.92; P < .001).
PHILO[8]	801 patients with ACS	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter)	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter)	12 months	Primary safety and efficacy endpoints were time to first occurrence of any major bleeding event and to any event from the composite of MI, stroke or death from vascular causes, respectively	At 12 months, overall major bleeding occurred in 10.3% of ticagrelor-treated patients and in 6.8% of clopidogrel-treated patients (HR 1.54; 95% CI 0.94–2.53); the composite primary efficacy endpoint occurred in 9.0% and in 6.3% of ticagrelor- and clopidogrel-treated patients, respectively (HR 1.47; 95% CI 0.88–2.44).
PEGASUS-TIMI54[10]	21,162 patients (65.4 years-old) who had a MI 1–3 years earlier	Ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily	Placebo	2.75 years	CV death, MI, or stroke	The rate of the primary efficacy end point, with Kaplan–Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (HR for 90 mg of ticagrelor vs. placebo, 0.85; 95% CI 0.75 to 0.96; P = .008; HR for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI 0.74 to 0.95; P = .004).
THEMIS[11]	19,220 patients who were 50 years of age or older and who had stable CAD and type 2 diabetes mellitus	Ticagrelor initially 90 mg then 60 mg twice daily plus aspirin	Placebo plus aspirin	39.9 months	CV death, MI, or stroke	The incidence of the primary efficacy outcome was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; HR 0.90; 95% CI 0.81–0.99; P = .04)
TICAKOREA[9]	800 Korean patients hospitalized for ACS with or without ST elevation and intended for invasive management	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter)	Clopidogrel (600 mg loading dose, 75 mg daily thereafter)	12 months	Clinically significant bleeding (composite of major bleeding or minor bleeding according to PLATO (Platelet Inhibition and Patient Outcomes) criteria at 12 months Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding	At 12 months, the incidence of clinically significant bleeding was significantly higher in the ticagrelor group than in the clopidogrel group (11.7% [45/400] vs 5.3% [21/400]; HR 2.26; 95% CI 1.34 to 3.79; P = .002). The incidence of death from CV causes, MI, or stroke was not significantly different between the ticagrelor group and the clopidogrel group (9.2% [36/400] vs 5.8% [23/400]; HR 1.62; 95% CI 0.96 to 2.74; P = .07).
ALPHEUS[12]	1,910 patients with stable coronary artery disease and had an indication for PCI and at least one high-risk characteristic	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days)	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter for 30 days)	48 hours	Composite of PCI-related type 4 (a or b) MI or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier).	At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (OR 0.97, 95% CI 0.80–1.17; P = .75)
POPular AGE[13]	1,002 Patients aged 70 years or older with NSTE-ACS	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) in 95% Prasugrel 60 mg loading dose, 10 mg daily thereafter) in 5%	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter)	12 months	Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis])	Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; HR 0.71, 95% CI 0.54 to 0.94; P = .02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; ARD −4%, 95% CI −10.0 to 1.4; P = .03 for non-inferiority)
TOPIC[16]	645 patients admitted with ACS requiring coronary intervention, on aspirin and a newer P2Y12 blocker (ticagrelor 43%, prasugrel 57%) and without adverse event at 1 month, were assigned to switch to aspirin and clopidogrel (switched DAPT) or continuation of their drug regimen (unchanged DAPT).	Continuation of their drug regimen (unchanged DAPT).	Switch to aspirin and clopidogrel (switched DAPT)	12 months	Composite of CV death, urgent revascularization, stroke and bleeding as defined by the Bleeding Academic Research Consortium (BARC) classification ≥2 at 1 year post ACS.	The primary endpoint occurred in 43 (13.4%) patients in the switched DAPT group and in 85 (26.3%) patients in the unchanged DAPT (HR 95%CI 0.48 (0.34–0.68), P < 0.01). No significant differences were reported on ischemic endpoints, while BARC ≥ 2 bleeding occurred in 13 (4.0%) patients in the switched DAPT and in 48 (14.9%) in the unchanged DAPT group (HR 95%CI 0.30 (0.18–0.50), P < .01)

Abbreviations ARD: absolute risk difference; FI: fragility index; MI: myocardial infarction; ACS: acute coronary syndrome; CV: cardiovascular; DAPT: dual antiplatelet therapy; HF: heart failure; HR: hazard ratio; LV: left ventricular; MI: myocardial infarction; NSTE: non ST elevation; NYHA: New York Heart Association; NNT: number needed to treat for the primary outcome during the mean duration follow-up of the study; OR: odds ratio

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