Trial Outcomes & Findings for Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients With Acute Myocardial Infarction (NCT NCT02217878)

NCT ID: NCT02217878

Last Updated: 2017-09-12

Results Overview

Exposure to ticagrelor during the first 12 hours after ticagrelor loading dose

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 74 participants
• Primary outcome timeframe: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose
• Results posted on: 2017-09-12

Participant Flow

Participant milestones

Measure	Morphine morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Overall Study STARTED	37	37
Overall Study COMPLETED	35	35
Overall Study NOT COMPLETED	2	2

Reasons for withdrawal

Measure	Morphine morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Overall Study required morphine due to chest pain	1	2
Overall Study initial diagnosis of STEMI not confirmed	1	0

Baseline Characteristics

Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients With Acute Myocardial Infarction

Baseline characteristics by cohort

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose	Total n=70 Participants Total of all reporting groups
Age, Continuous	60.7 years STANDARD_DEVIATION 10.5 • n=5 Participants	62.5 years STANDARD_DEVIATION 10.5 • n=7 Participants	61.5 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	7 Participants n=7 Participants	19 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	28 Participants n=7 Participants	51 Participants n=5 Participants
BMI	27.6 kg/m^2 STANDARD_DEVIATION 4.3 • n=5 Participants	27.4 kg/m^2 STANDARD_DEVIATION 4.0 • n=7 Participants	27.5 kg/m^2 STANDARD_DEVIATION 4.2 • n=5 Participants
STEMI	24 participants n=5 Participants	21 participants n=7 Participants	45 participants n=5 Participants
GP IIb/IIIa administration	10 participants n=5 Participants	6 participants n=7 Participants	16 participants n=5 Participants
Hypertension	15 participants n=5 Participants	21 participants n=7 Participants	36 participants n=5 Participants
Diabetes mellitus	8 participants n=5 Participants	5 participants n=7 Participants	13 participants n=5 Participants
Dyslipidaemia	30 participants n=5 Participants	31 participants n=7 Participants	61 participants n=5 Participants
Current smoker	17 participants n=5 Participants	14 participants n=7 Participants	31 participants n=5 Participants
Prior AMI	5 participants n=5 Participants	8 participants n=7 Participants	13 participants n=5 Participants
Prior PCI	4 participants n=5 Participants	9 participants n=7 Participants	13 participants n=5 Participants
Prior CABG	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Prior non-severe heart failure	0 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants
Prior non-haemorrhagic stroke	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Peripheral arterial disease	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
Chronic renal disease	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Chronic obstructive pulmonary disease	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Gout	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants

PRIMARY outcome

Timeframe: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose

Exposure to ticagrelor during the first 12 hours after ticagrelor loading dose

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)	6307 ng*h/mL Standard Deviation 4359	9791 ng*h/mL Standard Deviation 5136

SECONDARY outcome

Timeframe: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose

Exposure to ticagrelor metabolite during the first 12 hours after ticagrelor loading dose

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h)	1503 ng*h/mL Standard Deviation 1138	2388 ng*h/mL Standard Deviation 1555

SECONDARY outcome

Timeframe: 12 hours

Maximum concentration (Cmax) of ticagrelor

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Maximum Concentration of Ticagrelor	1156 ng/mL Standard Deviation 771	1683 ng/mL Standard Deviation 847

SECONDARY outcome

Timeframe: 12 hours

Maximum concentration (Cmax) of AR-C124910XX

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Maximum Concentration of AR-C124910XX	1085 ng/mL Interval 508.0 to 1709.0	1043 ng/mL Interval 792.0 to 1572.0

SECONDARY outcome

Timeframe: 12 hours

Time to maximum concentration (Tmax) for ticagrelor

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Time to Maximum Concentration for Ticagrelor	4 hours Interval 3.0 to 12.0	2 hours Interval 2.0 to 4.0

SECONDARY outcome

Timeframe: 12 hours

Time to maximum concentration (Tmax) for AR-C124910XX

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Time to Maximum Concentration for AR-C124910XX	4 hours Interval 3.0 to 12.0	4 hours Interval 3.0 to 6.0

SECONDARY outcome

Timeframe: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose

Exposure to ticagrelor during the first 6 hours after ticagrelor loading dose

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h)	2491 ng*h/mL Interval 189.0 to 5764.0	5587 ng*h/mL Interval 2810.0 to 8546.0

SECONDARY outcome

Timeframe: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose

Exposure to ticagrelor metabolite during the first 6 hours after ticagrelor loading dose

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6)	472 ng*h/mL Interval 0.0 to 1036.0	1001 ng*h/mL Interval 643.0 to 1666.0

SECONDARY outcome

Timeframe: prior to the initial ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	88.5 Platelet Reactivity Index (%) Interval 82.9 to 93.5	88.3 Platelet Reactivity Index (%) Interval 81.5 to 94.0

SECONDARY outcome

Timeframe: 30 minutes post ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	83.2 Platelet Reactivity Index (%) Interval 74.5 to 89.7	73.9 Platelet Reactivity Index (%) Interval 42.6 to 87.7

SECONDARY outcome

Timeframe: 1 hour post ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	70.2 Platelet Reactivity Index (%) Interval 34.1 to 87.2	42.0 Platelet Reactivity Index (%) Interval 25.6 to 81.2

SECONDARY outcome

Timeframe: 2 hours post ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	52.1 Platelet Reactivity Index (%) Interval 21.7 to 80.5	26.2 Platelet Reactivity Index (%) Interval 18.7 to 52.1

SECONDARY outcome

Timeframe: 3 hours post ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	37.8 Platelet Reactivity Index (%) Interval 24.7 to 75.1	26.0 Platelet Reactivity Index (%) Interval 13.1 to 52.4

SECONDARY outcome

Timeframe: 4 hours post ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	36.9 Platelet Reactivity Index (%) Interval 19.1 to 64.1	23.2 Platelet Reactivity Index (%) Interval 14.3 to 43.4

SECONDARY outcome

Timeframe: 6 hours post ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	27.9 Platelet Reactivity Index (%) Interval 18.2 to 44.1	19.7 Platelet Reactivity Index (%) Interval 12.7 to 33.0

SECONDARY outcome

Timeframe: 12 hours post ticagrelor dose

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Reactivity Index Assessed by VASP Assay	27.5 Platelet Reactivity Index (%) Interval 17.0 to 42.3	15.6 Platelet Reactivity Index (%) Interval 12.3 to 33.1

SECONDARY outcome

Timeframe: prior to the initial ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	85 Platelet Arbitrary Aggregation Units Interval 70.0 to 102.0	77 Platelet Arbitrary Aggregation Units Interval 54.0 to 95.0

SECONDARY outcome

Timeframe: 30 minutes post ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	86 Platelet Arbitrary Aggregation Units Interval 53.0 to 99.0	48 Platelet Arbitrary Aggregation Units Interval 22.0 to 89.0

SECONDARY outcome

Timeframe: 1 hour post ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	59 Platelet Arbitrary Aggregation Units Interval 31.0 to 86.0	23 Platelet Arbitrary Aggregation Units Interval 17.0 to 60.0

SECONDARY outcome

Timeframe: 2 hours post ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	31 Platelet Arbitrary Aggregation Units Interval 20.0 to 71.0	23 Platelet Arbitrary Aggregation Units Interval 10.0 to 36.0

SECONDARY outcome

Timeframe: 3 hours post ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	27 Platelet Arbitrary Aggregation Units Interval 18.0 to 55.0	17 Platelet Arbitrary Aggregation Units Interval 10.0 to 23.0

SECONDARY outcome

Timeframe: 4 hours post ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	29 Platelet Arbitrary Aggregation Units Interval 10.0 to 44.0	13 Platelet Arbitrary Aggregation Units Interval 9.0 to 22.0

SECONDARY outcome

Timeframe: 6 hours post ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	19 Platelet Arbitrary Aggregation Units Interval 9.0 to 34.0	11 Platelet Arbitrary Aggregation Units Interval 5.0 to 15.0

SECONDARY outcome

Timeframe: 12 hours post ticagrelor dose

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	19 Platelet Arbitrary Aggregation Units Interval 10.0 to 27.0	11 Platelet Arbitrary Aggregation Units Interval 7.0 to 16.0

SECONDARY outcome

Timeframe: prior to the initial ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	232.5 P2Y12 Reaction Units Interval 197.0 to 270.0	238.5 P2Y12 Reaction Units Interval 194.0 to 267.0

SECONDARY outcome

Timeframe: 30 minutes post ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	268.5 P2Y12 Reaction Units Interval 202.0 to 299.0	210.5 P2Y12 Reaction Units Interval 118.0 to 266.0

SECONDARY outcome

Timeframe: 1 hour post ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	206.5 P2Y12 Reaction Units Interval 88.0 to 266.0	117.0 P2Y12 Reaction Units Interval 10.0 to 233.0

SECONDARY outcome

Timeframe: 2 hours post ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	137.0 P2Y12 Reaction Units Interval 27.0 to 251.0	44.0 P2Y12 Reaction Units Interval 7.0 to 119.0

SECONDARY outcome

Timeframe: 3 hours post ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	113.0 P2Y12 Reaction Units Interval 31.0 to 221.0	15.0 P2Y12 Reaction Units Interval 4.0 to 52.0

SECONDARY outcome

Timeframe: 4 hours post ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	50.5 P2Y12 Reaction Units Interval 8.0 to 165.0	9.0 P2Y12 Reaction Units Interval 4.0 to 72.0

SECONDARY outcome

Timeframe: 6 hours post ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	44.5 P2Y12 Reaction Units Interval 6.0 to 171.0	8.0 P2Y12 Reaction Units Interval 3.0 to 21.0

SECONDARY outcome

Timeframe: 12 hours post ticagrelor dose

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
P2Y12 Reaction Units Assessed by VerifyNow	9.0 P2Y12 Reaction Units Interval 4.0 to 116.0	7.5 P2Y12 Reaction Units Interval 3.0 to 48.0

SECONDARY outcome

Timeframe: 2 hours

Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VASP

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP	57 Percentage of Patients With HPR	29 Percentage of Patients With HPR

SECONDARY outcome

Timeframe: 2 hours

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With MEA

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA	40 Percentage of Patients With HPR	14 Percentage of Patients With HPR

SECONDARY outcome

Timeframe: 2 hours

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VerifyNow

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow	36 Percentage of Patients With HPR	19 Percentage of Patients With HPR

SECONDARY outcome

Timeframe: 12 hours

Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VASP

Outcome measures

Measure	Morphine n=35 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP	2.0 hours Interval 1.0 to 6.0	1 hours Interval 0.5 to 3.0

SECONDARY outcome

Timeframe: 12 hours

Population: According to the study protocol multiple electrode aggregometry pharmacodynamic evaluation was performed in all patients except for those treated with glycoprotein (GP) IIb/IIIa receptor inhibitors.

Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With MEA

Outcome measures

Measure	Morphine n=25 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=29 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA	2.0 hours Interval 1.0 to 4.0	1.0 hours Interval 0.5 to 2.0

SECONDARY outcome

Timeframe: 12 hours

Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.

Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VerifyNow

Outcome measures

Measure	Morphine n=26 Participants morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 Participants sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow	1.0 hours Interval 0.0 to 3.0	0.5 hours Interval 0.0 to 1.0

Adverse Events

Morphine

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Measure	Morphine n=35 participants at risk morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 participants at risk sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Vascular disorders Stent thrombosis	2.9% 1/35 • 7 days	0.00% 0/35 • 7 days
Cardiac disorders Pulmonary oedema	0.00% 0/35 • 7 days	5.7% 2/35 • 7 days

Other adverse events

Measure	Morphine n=35 participants at risk morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor Morphine: IV bolus injection Ticagrelor: 180 mg loading dose	Placebo n=35 participants at risk sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor Placebo: IV bolus injection Ticagrelor: 180 mg loading dose
Vascular disorders TIMI minor bleeding	0.00% 0/35 • 7 days	11.4% 4/35 • 7 days
Vascular disorders TIMI minimal bleeding	0.00% 0/35 • 7 days	2.9% 1/35 • 7 days
Cardiac disorders Bradyarrhythmic event	2.9% 1/35 • 7 days	5.7% 2/35 • 7 days
Gastrointestinal disorders Nausea	5.7% 2/35 • 7 days	0.00% 0/35 • 7 days
Gastrointestinal disorders Vomiting	5.7% 2/35 • 7 days	0.00% 0/35 • 7 days

Additional Information

Prof. Jacek Kubica

Collegium Medicum, Nicolaus Copernicus University

Phone: +485854023

Email: jkubica@cm.umk.pl

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place