Non-ST-segment Elevation Myocardial Infarction, ST-segment Elevation Myocardial Infarction, VA Drug Interactions
Conditions
Keywords
ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, ticagrelor, morphine, pharmacokinetics, pharmacodynamics, drug interactions, VASP assay, Multiple Electrode Aggregometry, VerifyNow
Brief summary
The purpose of the IMPRESSION study is to determine whether intravenous administration of morphine prior to ticagrelor administration in ST-segment elevation myocardial infarction (STEMI) patients and in non-ST-segment elevation myocardial infarction (NSTEMI) patients alters the plasma concentrations of ticagrelor and its active metabolite and whether it is associated with any negative impact on the antiplatelet effect of ticagrelor.
Detailed description
The European Society of Cardiology and American Heart Association guidelines recommend use of morphine as a treatment of choice for pain relief in STEMI patients. However, this recommendation, although strong, is only based on expert consensus (class of recommendation I, level of evidence C). Morphine, apart from its analgesic effects, also alleviates the work of breathing and reduces anxiety. On the other hand, despite its favorable analgesic and sedative actions, morphine also exerts adverse effects, which include hypotension, bradycardia, respiratory depression, vomiting and reduction of gastrointestinal motility. Some of the previously listed morphine's side effects could affect the intestinal absorption and thus pharmacokinetics and pharmacodynamics of orally administered drugs which are concomitantly used with morphine. At present, no pharmacokinetic and pharmacodynamic data regarding the concurrent use of morphine and P2Y12 blockers in the STEMI or NSTEMI setting are available. Therefore, evidence-based verification of morphine's influence on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) could provide a valuable insight in the knowledge regarding modern acute myocardial infarction management. Predefined subanalysis: aimed to investigate which one of platelet reactivity assessment methods utilized in the study (VASP assay, MEA, LTA, VerifyNow) best reflects concentration of ticagrelor and its active metabolite (AR-C124910XX). Since there is no reference study examining pharmacokinetics of ticagrelor in STEMI or NSTEMI patients, we decided to perform an internal pilot study of approximately 30 patients (15 patients for each arm) for estimating the final sample size.
Interventions
DRUGMorphine
IV bolus injection
DRUGPlacebo
IV bolus injection
DRUGTicagrelor
180 mg loading dose
Sponsors
Collegium Medicum w Bydgoszczy
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* provision of informed consent prior to any study specific procedures * diagnosis of acute ST-segment elevation myocardial infarction or acute non-ST-segment elevation myocardial infarction * male or non-pregnant female, aged 18-80 years old * provision of informed consent for angiography and PCI
Exclusion criteria
* chest pain described by the patient as unbearable or patient's request for analgesics * prior morphine administration during the current STEMI or NSTEMI * treatment with ticlopidine, clopidogrel, prasugrel or ticagrelor within 14 days before the study enrollment * hypersensitivity to ticagrelor * current treatment with oral anticoagulant or chronic therapy with low-molecular-weight heparin * active bleeding * history of intracranial hemorrhage * recent gastrointestinal bleeding (within 30 days) * history of coagulation disorders * platelet count less than \<100 x10\^3/mcl * hemoglobin concentration less than 10.0 g/dl * history of moderate or severe hepatic impairment * history of major surgery or severe trauma (within 3 months) * patients considered by the investigator to be at risk of bradycardic events * second or third degree atrioventricular block during screening for eligibility * history of asthma or severe chronic obstructive pulmonary disease * patient required dialysis * manifest infection or inflammatory state * Killip class III or IV during screening for eligibility * respiratory failure * history of severe chronic heart failure (NYHA class III or IV) * concomitant therapy with strong CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir) or strong CYP3A inducers (rifampicin, phenytoin, carbamazepine, dexamethasone, phenobarbital) within 14 days and during study treatment * body weight below 50 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration of Ticagrelor | 12 hours | Maximum concentration (Cmax) of ticagrelor |
| Maximum Concentration of AR-C124910XX | 12 hours | Maximum concentration (Cmax) of AR-C124910XX |
| Time to Maximum Concentration for Ticagrelor | 12 hours | Time to maximum concentration (Tmax) for ticagrelor |
| Time to Maximum Concentration for AR-C124910XX | 12 hours | Time to maximum concentration (Tmax) for AR-C124910XX |
| Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h) | 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 |
| Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6) | 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 |
| Platelet Reactivity Index Assessed by VASP Assay | prior to the initial ticagrelor dose | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%) |
| Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h) | 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 |
| P2Y12 Reaction Units Assessed by VerifyNow | prior to the initial ticagrelor dose | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208) |
| Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP | 2 hours | Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VASP |
| Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA | 2 hours | Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With MEA |
| Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow | 2 hours | Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VerifyNow |
| Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP | 12 hours | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VASP |
| Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA | 12 hours | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With MEA |
| Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow | 12 hours | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VerifyNow |
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | prior to the initial ticagrelor dose | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units) |
Countries
Poland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Morphine morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor
Morphine: IV bolus injection
Ticagrelor: 180 mg loading dose | 35 |
| 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 | 35 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | initial diagnosis of STEMI not confirmed | 1 | 0 |
| Overall Study | required morphine due to chest pain | 1 | 2 |
Baseline characteristics
| Characteristic | Morphine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 10.5 | 61.5 years STANDARD_DEVIATION 10.3 | 62.5 years STANDARD_DEVIATION 10.5 |
| BMI | 27.6 kg/m^2 STANDARD_DEVIATION 4.3 | 27.5 kg/m^2 STANDARD_DEVIATION 4.2 | 27.4 kg/m^2 STANDARD_DEVIATION 4 |
| Chronic obstructive pulmonary disease | 2 participants | 2 participants | 0 participants |
| Chronic renal disease | 1 participants | 3 participants | 2 participants |
| Current smoker | 17 participants | 31 participants | 14 participants |
| Diabetes mellitus | 8 participants | 13 participants | 5 participants |
| Dyslipidaemia | 30 participants | 61 participants | 31 participants |
| Gout | 1 participants | 3 participants | 2 participants |
| GP IIb/IIIa administration | 10 participants | 16 participants | 6 participants |
| Hypertension | 15 participants | 36 participants | 21 participants |
| Peripheral arterial disease | 3 participants | 4 participants | 1 participants |
| Prior AMI | 5 participants | 13 participants | 8 participants |
| Prior CABG | 0 participants | 0 participants | 0 participants |
| Prior non-haemorrhagic stroke | 1 participants | 1 participants | 0 participants |
| Prior non-severe heart failure | 0 participants | 3 participants | 3 participants |
| Prior PCI | 4 participants | 13 participants | 9 participants |
| Sex: Female, Male Female | 12 Participants | 19 Participants | 7 Participants |
| Sex: Female, Male Male | 23 Participants | 51 Participants | 28 Participants |
| STEMI | 24 participants | 45 participants | 21 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 35 | 7 / 35 |
| serious Total, serious adverse events | 1 / 35 | 2 / 35 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)
Exposure to ticagrelor during the first 12 hours after ticagrelor loading dose
Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine | Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h) | 6307 ng*h/mL | Standard Deviation 4359 |
| Placebo | Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h) | 9791 ng*h/mL | Standard Deviation 5136 |
Secondary
Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h)
Exposure to ticagrelor metabolite during the first 12 hours after ticagrelor loading dose
Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine | Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h) | 1503 ng*h/mL | Standard Deviation 1138 |
| Placebo | Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h) | 2388 ng*h/mL | Standard Deviation 1555 |
Secondary
Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6)
Exposure to ticagrelor metabolite during the first 6 hours after ticagrelor loading dose
Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6) | 472 ng*h/mL |
| Placebo | Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6) | 1001 ng*h/mL |
Secondary
Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h)
Exposure to ticagrelor during the first 6 hours after ticagrelor loading dose
Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h) | 2491 ng*h/mL |
| Placebo | Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h) | 5587 ng*h/mL |
Secondary
Maximum Concentration of AR-C124910XX
Maximum concentration (Cmax) of AR-C124910XX
Time frame: 12 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Maximum Concentration of AR-C124910XX | 1085 ng/mL |
| Placebo | Maximum Concentration of AR-C124910XX | 1043 ng/mL |
Secondary
Maximum Concentration of Ticagrelor
Maximum concentration (Cmax) of ticagrelor
Time frame: 12 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine | Maximum Concentration of Ticagrelor | 1156 ng/mL | Standard Deviation 771 |
| Placebo | Maximum Concentration of Ticagrelor | 1683 ng/mL | Standard Deviation 847 |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: prior to the initial ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 232.5 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 238.5 P2Y12 Reaction Units |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: 1 hour post ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 206.5 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 117.0 P2Y12 Reaction Units |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: 30 minutes post ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 268.5 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 210.5 P2Y12 Reaction Units |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: 12 hours post ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 9.0 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 7.5 P2Y12 Reaction Units |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: 6 hours post ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 44.5 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 8.0 P2Y12 Reaction Units |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: 4 hours post ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 50.5 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 9.0 P2Y12 Reaction Units |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: 3 hours post ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 113.0 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 15.0 P2Y12 Reaction Units |
Secondary
P2Y12 Reaction Units Assessed by VerifyNow
P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Time frame: 2 hours post ticagrelor dose
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | P2Y12 Reaction Units Assessed by VerifyNow | 137.0 P2Y12 Reaction Units |
| Placebo | P2Y12 Reaction Units Assessed by VerifyNow | 44.0 P2Y12 Reaction Units |
Secondary
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA
Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With MEA
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Morphine | Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA | 40 Percentage of Patients With HPR |
| Placebo | Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA | 14 Percentage of Patients With HPR |
Secondary
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP
Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VASP
Time frame: 2 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Morphine | Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP | 57 Percentage of Patients With HPR |
| Placebo | Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP | 29 Percentage of Patients With HPR |
Secondary
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow
Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VerifyNow
Time frame: 2 hours
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Morphine | Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow | 36 Percentage of Patients With HPR |
| Placebo | Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow | 19 Percentage of Patients With HPR |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 19 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 11 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 85 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 77 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 86 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 48 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 59 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 23 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 31 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 23 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 27 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 17 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 29 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 13 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 19 Platelet Arbitrary Aggregation Units |
| Placebo | Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | 11 Platelet Arbitrary Aggregation Units |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: prior to the initial ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 88.5 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 88.3 Platelet Reactivity Index (%) |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: 6 hours post ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 27.9 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 19.7 Platelet Reactivity Index (%) |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: 4 hours post ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 36.9 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 23.2 Platelet Reactivity Index (%) |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: 3 hours post ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 37.8 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 26.0 Platelet Reactivity Index (%) |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: 2 hours post ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 52.1 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 26.2 Platelet Reactivity Index (%) |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: 1 hour post ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 70.2 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 42.0 Platelet Reactivity Index (%) |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: 30 minutes post ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 83.2 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 73.9 Platelet Reactivity Index (%) |
Secondary
Platelet Reactivity Index Assessed by VASP Assay
Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
Time frame: 12 hours post ticagrelor dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Platelet Reactivity Index Assessed by VASP Assay | 27.5 Platelet Reactivity Index (%) |
| Placebo | Platelet Reactivity Index Assessed by VASP Assay | 15.6 Platelet Reactivity Index (%) |
Secondary
Time to Maximum Concentration for AR-C124910XX
Time to maximum concentration (Tmax) for AR-C124910XX
Time frame: 12 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Time to Maximum Concentration for AR-C124910XX | 4 hours |
| Placebo | Time to Maximum Concentration for AR-C124910XX | 4 hours |
Secondary
Time to Maximum Concentration for Ticagrelor
Time to maximum concentration (Tmax) for ticagrelor
Time frame: 12 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Time to Maximum Concentration for Ticagrelor | 4 hours |
| Placebo | Time to Maximum Concentration for Ticagrelor | 2 hours |
Secondary
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With MEA
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA | 2.0 hours |
| Placebo | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA | 1.0 hours |
Secondary
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VASP
Time frame: 12 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP | 2.0 hours |
| Placebo | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP | 1 hours |
Secondary
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VerifyNow
Time frame: 12 hours
Population: In line with the study protocol, VerifyNow pharmacodynamic evaluation involved \>30% of the overall study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow | 1.0 hours |
| Placebo | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow | 0.5 hours |