Coronary Artery Disease
Conditions
Brief summary
Ticagrelor is associated with more prompt and potent antiplatelet effects compared with clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality, across the spectrum of patients with acute coronary syndrome, including those with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, in this latter setting a delay in the onset of its antiplatelet effects has been shown. Morphine has been identified as a cause of delayed P2Y12 inhibition in patients with STEMI. Methylnaltrexone is a parenteral peripheral opioid receptor antagonist which has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. However, whether the use of intravenous methylnaltrexone may overcome the effects of morphine administration on the pharmacokinetic (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been investigated yet. The proposed investigation will include patients with coronary artery disease and will have a prospective, randomized, cross-over design.
Detailed description
Ticagrelor is associated with more prompt and potent antiplatelet effects compared with clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality, across the spectrum of patients with acute coronary syndrome, including those with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, in this latter setting a delay in the onset of its antiplatelet effects has been shown. Morphine has been identified as a cause of delayed P2Y12 inhibition in patients with STEMI. In fact, opiates are known to inhibit gastric emptying, leading to delayed absorption and potentially decreasing peak plasma levels of orally administered drugs. Methylnaltrexone is a parenteral peripheral opioid receptor antagonist which has the potential to prevent or reverse opioid-induced peripherally mediated side effects (i.e. gastric emptying inhibition) without affecting analgesia. Studies have shown that methylnaltrexone effectively prevented morphine-induced gut motility change. However, whether the use of intravenous methylnaltrexone may overcome the effects of morphine administration on the pharmacokinetic (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been investigated yet. The proposed investigation will include patients with coronary artery disease and will have a prospective, randomized, cross-over design. Patients will be randomized to receive either intravenous methylnaltrexone or placebo. Immediately after methylnaltrexone administration, patients will receive intravenous morphine and then will receive a 180-mg ticagrelor loading dose 15 minutes after morphine administration. After a 7 ± 2 days wash-out period, patients will cross-over to the alternate study-treatment arm. At each visit, blood samples for PK and PD assessments will be collected at several time points. This study will provide insights on a possible treatment strategy to overcome the impaired P2Y12 inhibition induced by morphine.
Interventions
DRUGMethylnaltrexone
Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus
OTHERPlacebo
Placebo will be administered as a 0.9% sodium chloride iv injection
DRUGMorphine
After methylnaltrexone, patients will receive 5-mg intravenous morphine
DRUGTicagrelor
After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with angiographically documented CAD. * On treatment with low-dose aspirin (81 mg) for at least 30 days, as per standard of care. * Age between 18 and 80 years old.
Exclusion criteria
* History of prior intracranial bleeding. * On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) or with vorapaxar in past 30 days. * Known allergies to ticagrelor. * On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban). * Treatment with glycoprotein IIb/IIIa inhibitors in past 7 days. * Known blood dyscrasia or bleeding diathesis. * Platelet count \<80x106/mL. * Hemoglobin \<10 g/dL. * Active bleeding. * Hemodynamic instability. * Creatinine clearance \<30 mL/minute (as estimated by Cockcroft-Gault formula). * Severe hepatic dysfunction. * Acute or severe bronchial asthma or upper airway obstruction. * Known or suspected mechanical gastrointestinal obstruction. * Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection. * Current treatment with any drug interfering with morphine: central nervous system depressants (other narcotic analgesics, general anesthetics, phenothiazines, tricyclic antidepressants, tranquilizers, sedatives, hypnotics, antiemetics, and alcohol), muscle relaxants, mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol), cimetidine, monoamine oxidase inhibitors (MAOIs), anticholinergics. * Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin. * Pregnant females\*. \*Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Measured by VerifyNow P2Y12 | 2 hours | Platelet reactivity measured by VerifyNow P2Y12 2 hours after ticagrelor loading dose and reported as P2Y12 reaction units (PRU) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Measured by VASP | 2 hours | Platelet reactivity measured by VASP 2 hours after ticagrelor loading dose and reported as platelet reactivity index (PRI) |
| AUC of Ticagrelor Plasma Levels | 6 hours | The area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC) was calculated based on ticagrelor plasma levels |
Countries
United States
Participant flow
Recruitment details
Between August 2015 and April 2016 a total of 34 patients were recruited and consented at the University of Florida Health Science Center at UF Health Jacksonville - Division of Cardiology.
Pre-assignment details
Four subjects withdrew their consent before randomization and did not receive study drug. Therefore a total of 30 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Whole Study Population Patients were randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection). Methylnaltrexone, at a dose of 0.3 mg/Kg, was administered diluted with 5 ml of normal saline as a single i.v. bolus over 1 minute followed by morphine (5-mg intravenous bolus). Then patients received iv morphine and a loading dose of ticagrelor. After a 7 ± 2 days wash-out period, patients crossed-over to the alternate study-treatment arm. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Whole Study Population |
|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 29 |
| other Total, other adverse events | 8 / 30 | 10 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 29 |
Outcome results
Primary
Platelet Reactivity Measured by VerifyNow P2Y12
Platelet reactivity measured by VerifyNow P2Y12 2 hours after ticagrelor loading dose and reported as P2Y12 reaction units (PRU)
Time frame: 2 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methylnaltrexone | Platelet Reactivity Measured by VerifyNow P2Y12 | 130 PRU |
| Placebo | Platelet Reactivity Measured by VerifyNow P2Y12 | 97 PRU |
p-value: 0.26195% CI: [-90, 25]Mixed Models Analysis
Secondary
AUC of Ticagrelor Plasma Levels
The area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC) was calculated based on ticagrelor plasma levels
Time frame: 6 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Methylnaltrexone | AUC of Ticagrelor Plasma Levels | 2952 ng*hr/mL |
| Placebo | AUC of Ticagrelor Plasma Levels | 2276 ng*hr/mL |
Secondary
Platelet Reactivity Measured by VASP
Platelet reactivity measured by VASP 2 hours after ticagrelor loading dose and reported as platelet reactivity index (PRI)
Time frame: 2 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methylnaltrexone | Platelet Reactivity Measured by VASP | 47 PRI |
| Placebo | Platelet Reactivity Measured by VASP | 40 PRI |