NSTEMI - Non-ST Segment Elevation MI, ST Elevation Myocardial Infarction
Conditions
Brief summary
Randomized clinical study evaluating superiority in platelet inhibition after administration of Ticagrelor 180 mg loading dose as an orodispersible formulation versus traditional coated tablets in patients admitted for ST elevation myocardial infarction or very high-risk non-ST elevation myocardial infarction.
Detailed description
Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for patients with acute ST-segment elevation myocardial infarction (STEMI). Additional antithrombotic therapy prior or during intervention plays an important role in the short- and long-term outcomes after PPCI. Oral antiplatelet therapy including a platelet P2Y12 receptor inhibitors is a cornerstone of antithrombotic treatment in patients with acute coronary syndromes. Prasugrel and Ticagrelor have been shown to be superior to Clopidogrel in patients with STEMI in reduction of ischemic complication without any increase in the bleeding risk and with a significant reduction in the stent thrombosis rate. Nevertheless, in STEMI patients, pharmacodynamic studies showed prasugrel and ticagrelor oral loading dose (LD) provided a suboptimal platelet inhibition in the first hours after LD, and at least 4 hours are required to achieve and effective platelet aggregation inhibition in the majority of patients, in part due to slowed gut motility caused by morphine use. Orodispersible tablet (ODT) is a different tablet formulation that disperses upon contact with the moist mucosal surfaces of the oral cavity and quickly release its components before swallowing; thus local drug dissolution and absorption as well as onset of clinical effect can be obtained conveniently easily and quickly by bypassing gastrointestinal tract. Recently, Ticagrelor 90 mg ODT has become available and bioequivalence studies on healthy volunteers documented its effectiveness with consequent approval by European Medicine Agency of this formulation which is currently available on the market. Thus, the aim of the present study is to evaluate the superiority in platelet inhibition with 180 mg Ticagrelor loading dose (LD) administered as ODTs as compared with standard formulation, among patients with STEMI or very high-risk NSTEMI undergoing immediate PCI. Primary objective consists in evaluating platelet reactivity 1 hour after Ticagrelor loading dose by VerifyNow test.
Interventions
DRUGTicagrelor orodispersible tablets
Ticagrelor loading dose (180 mg) given as two orodispersible tablets (each of 90 mg), to be dispersed in saliva.
DRUGTicagrelor standard tablets
Ticagrelor loading dose (180 mg) given as two standard coated tablets (each of 90 mg) to be swallowed with water.
Sponsors
AstraZeneca
Azienda Ospedaliero Universitaria di Sassari
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Masking description
Site investigators performing platelet function tests will be blinded regarding patient randomization arm and the blood samples will be fully anonymized.
Intervention model description
Comparison of platelet inhibition at different timepoints between 65 patients in the treatment arm (receiving orodispersible formulation of ticagrelor loading dose) versus 65 patients in the control arm (receiving standard coated formulation of ticagrelor loading dose). Randomization will be further stratified according to morphine use.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients presenting within 12 hours from the onset of symptoms with STEMI or very high-risk NSTEMI referred for immediate (\< 2 hours) angiography. Very high-risk NSTEMI patients include patients with haemodynamic instability or cardiogenic shock, heart failure, life-threatening arrhythmias or resuscitated cardiac arrest, intermittent ST-segment elevation, or ongoing chest pain. 2. Informed, written consent 3. Male or female patients, aged ≥ 18 years old
Exclusion criteria
1. Age \< 18 years 2. Active bleeding; bleeding diathesis; coagulopathy 3. History of gastrointestinal or genitourinary bleeding \<2 months 4. Major surgery in the last 6 weeks 5. History of intracranial bleeding or structural abnormalities 6. Suspected aortic dissection 7. Administration in the week before the index event of clopidogrel, ticlopidine, prasugrel, ticagrelor, thrombolytics, bivalirudin, low-molecular weight heparin or fondaparinux. 8. Concomitant oral or IV therapy with strong CYP3A inhibitors or strong CYP3A inducers, CYP3A with narrow therapeutic window 9. Known relevant hematological deviations: Hb \<10 g/dl, Thromb. \<100x10\^9/l 10. Use of warfarin or new oral anticoagulant derivatives within the last 7 days 11. Known severe liver disease, severe renal failure 12. Allergy or hypersensitivity to ticagrelor or any of the excipients. 13. Pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Platelet Inhibition | 1 hour | Platelet reactivity will be measured by VerifyNow test 1 hour after Ticagrelor loading dose (LD) administered as orodispersible tablets as compared with standard formulation in 130 patients with STEMI or very high-risk NSTEMI undergoing immediate PCI. The VerifyNow PRU Test is designed to measure P2Y12 receptor blockade. Results of the PRU Tests are reported as P2Y12 Reaction Units (PRU). PRU measures the extent of platelet aggregation in the presence of a P2Y12 inhibitor. Lower PRU levels are associated with expected antiplatelet effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Patients With Insufficient Antiaggregation | 1 hour | The percent of patients with a high residual platelet reactivity (PRU \> 208 by VerifyNow test), thus not adequately antiaggregated, 1 hour after Ticagrelor LD. |
| Number of Participants With Residual Platelet Reactivity at Various Timepoints | 2, 4 and 6 hours | Residual platelet reactivity (PRU) at 2, 4 and 6 hours measured by VerifyNow test to assess antiplatelet effect of P2Y12 inhibitors |
| Number of Participants With Clinically Relevant Bleeding Events | 30 days | Actionable bleeding events across the two different regimens of Ticagrelor administration, requiring diagnostic studies, hospitalization, or treatment by a health care professional (BARC type 2 or higher) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Morphine-ticagrelor Interaction | 6 hours | Potential morphine-ticagrelor interaction will be assessed by stratified randomization according to morphine use |
| Incidence of Adverse Events Occurring During Hospital Stay | Until discharge from the hospital (usually up to 7 days) | Combined ticagrelor administration-related adverse events defined as in-hospital ≥2 BARC bleedings, dyspnea, ventricular pauses, allergic reactions, or vomit |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor Orodispersible Tablets STEMI or very high-risk NSTEMI patients undergoing primary PCI and receiving Ticagrelor 180 mg loading dose as orodispersible tablets.
Intervention: administration of Ticagrelor 180 mg loading dose as orodispersible tablets.
Ticagrelor orodispersible tablets: Ticagrelor loading dose (180 mg) given as two orodispersible tablets (each of 90 mg), to be dispersed in saliva. | 65 |
| Ticagrelor Standard Tablets STEMI or very high-risk NSTEMI patients undergoing primary PCI and receiving Ticagrelor 180 mg loading dose as standard coated tablets.
Intervention: administration of Ticagrelor 180 mg loading dose as standard coated pills.
Ticagrelor pills: Ticagrelor loading dose (180 mg) given as two standard coated tablets (each of 90 mg) to be swallowed with water. | 65 |
| Total | 130 |
Baseline characteristics
| Characteristic | Ticagrelor Standard Tablets | Total | Ticagrelor Orodispersible Tablets |
|---|---|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 10 | 63.5 years STANDARD_DEVIATION 10 | 64.0 years STANDARD_DEVIATION 10 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 65 Participants | 130 Participants | 65 Participants |
| Sex: Female, Male Female | 17 Participants | 25 Participants | 8 Participants |
| Sex: Female, Male Male | 48 Participants | 105 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 65 |
| other Total, other adverse events | 14 / 65 | 15 / 65 |
| serious Total, serious adverse events | 1 / 65 | 0 / 65 |
Outcome results
Primary
Evaluation of Platelet Inhibition
Platelet reactivity will be measured by VerifyNow test 1 hour after Ticagrelor loading dose (LD) administered as orodispersible tablets as compared with standard formulation in 130 patients with STEMI or very high-risk NSTEMI undergoing immediate PCI. The VerifyNow PRU Test is designed to measure P2Y12 receptor blockade. Results of the PRU Tests are reported as P2Y12 Reaction Units (PRU). PRU measures the extent of platelet aggregation in the presence of a P2Y12 inhibitor. Lower PRU levels are associated with expected antiplatelet effect.
Time frame: 1 hour
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ticagrelor Orodispersible Tablets | Evaluation of Platelet Inhibition | 94 P2Y12 Reaction Units (PRU) |
| Ticagrelor Standard Tablets | Evaluation of Platelet Inhibition | 141 P2Y12 Reaction Units (PRU) |
Secondary
Number of Participants With Clinically Relevant Bleeding Events
Actionable bleeding events across the two different regimens of Ticagrelor administration, requiring diagnostic studies, hospitalization, or treatment by a health care professional (BARC type 2 or higher)
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor Orodispersible Tablets | Number of Participants With Clinically Relevant Bleeding Events | 0 Participants |
| Ticagrelor Standard Tablets | Number of Participants With Clinically Relevant Bleeding Events | 4 Participants |
Secondary
Number of Participants With Residual Platelet Reactivity at Various Timepoints
Residual platelet reactivity (PRU) at 2, 4 and 6 hours measured by VerifyNow test to assess antiplatelet effect of P2Y12 inhibitors
Time frame: 2, 4 and 6 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor Orodispersible Tablets | Number of Participants With Residual Platelet Reactivity at Various Timepoints | 42 Participants |
| Ticagrelor Standard Tablets | Number of Participants With Residual Platelet Reactivity at Various Timepoints | 9 Participants |
Secondary
Percent of Patients With Insufficient Antiaggregation
The percent of patients with a high residual platelet reactivity (PRU \> 208 by VerifyNow test), thus not adequately antiaggregated, 1 hour after Ticagrelor LD.
Time frame: 1 hour
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor Orodispersible Tablets | Percent of Patients With Insufficient Antiaggregation | 51 Participants |
| Ticagrelor Standard Tablets | Percent of Patients With Insufficient Antiaggregation | 53 Participants |
Other Pre-specified
Incidence of Adverse Events Occurring During Hospital Stay
Combined ticagrelor administration-related adverse events defined as in-hospital ≥2 BARC bleedings, dyspnea, ventricular pauses, allergic reactions, or vomit
Time frame: Until discharge from the hospital (usually up to 7 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor Orodispersible Tablets | Incidence of Adverse Events Occurring During Hospital Stay | 14 Participants |
| Ticagrelor Standard Tablets | Incidence of Adverse Events Occurring During Hospital Stay | 15 Participants |
Other Pre-specified
Number of Participants With Morphine-ticagrelor Interaction
Potential morphine-ticagrelor interaction will be assessed by stratified randomization according to morphine use
Time frame: 6 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor Orodispersible Tablets | Number of Participants With Morphine-ticagrelor Interaction | 6 Participants |
| Ticagrelor Standard Tablets | Number of Participants With Morphine-ticagrelor Interaction | 4 Participants |