Critical Limb Ischemia
Conditions
Keywords
Critical Limb Ischemia, ticagrelor, Brilinta
Brief summary
Critical Limb Ischemia (CLI) is defined as limb pain that occurs at rest, or impending limb loss that is caused by severe compromise of blood flow to the affected extremity. CLI is a major cause of death and disability (secondary to myocardial infarction, stroke and amputation). The mortality in patients with CLI approaches 13-25% and 50% at one and five years respectively. High on-treatment platelet reactivity (HPR) in patients treated with aspirin and clopidogrel is associated with increased risk of recurrent cardiovascular events after percutaneous coronary interventions and coronary syndromes. Preliminary studies suggest that the prevalence of HPR in patients with critical limb ischemia treated with aspirin and clopidogrel is as high a 78.5%. In patients with coronary artery disease ticagrelor overcomes non-responsiveness to clopidogrel. However, the antiplatelet effect of ticagrelor in patients with critical limb ischemia is unknown.
Detailed description
Study Aim: This pilot study aims to investigate platelet function after switching from clopidogrel to ticagrelor in patients with critical limb ischemia. Fifty patients with diagnosis of CLI (Rutherford class IV-VI) treated with clopidogrel 75 mg and aspirin 81 mg daily will be tested for inhibition of platelet aggregation using the VerifyNow P2Y12 and VASP assays before and 6±1 hours after their daily clopidogrel dose. All patients will then be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and Vasodilator-Stimulated Phosphoprotein (VASP) platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose. For exploratory analysis, patients will be divided in two groups based on the P2Y12 reaction units (PRU): Group 1. High on treatment platelet reactivity on clopidogrel (HPR), defined as P2Y12 reaction units (PRU) ≥208 and Group 2. Appropriate platelet inhibition on clopidogrel (API), defined as P2Y12 reaction units (PRU) \<208. If subjects are withdrawn from the study prior to completion due to the high co-morbidity rate of this population, additional subjects will be enrolled to reach a total of 50 completed subjects for data analysis.
Interventions
DRUGTicagrelor
All patients will be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and VASP platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose.
Sponsors
University of Southern California
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SCREENING
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients with diagnosis of CLI (Rutherford class IV, V and VI) on continuous dual antiplatelet therapy with aspirin 81 mg and clopidogrel 75 mg daily for at least 14+2 days .
Exclusion criteria
* Chronic use of nonsteroidal anti-inflammatory drugs, thrombocytopenia (platelet count \<100 × 103/μl), hemoglobin \<10 g/dL, use of an oral anticoagulant (warfarin) or low molecular weight heparin within 14 days, GPIIb/IIIa inhibitors, or fibrinolytic drugs within 30 days. Pregnancy, \<18 or \>80 years of age, current smoking (\>1 pack per day), concomitant therapy with strong cytochrome P450 3A inhibitors or inducers within 14 days, concomitant antithrombotic therapy other than aspirin within 14 days, hypercoaguable states. History of medication non-compliance, drug or alcohol abuse within 2 years. Acute coronary syndrome or coronary drug-eluting stenting within 1 year. Peripheral vascular revascularization procedures (surgical or endovascular) and/or amputation within one month. Contraindications for ticagrelor including: hypersensitivity to ticagrelor or any of the excipients, Active pathological bleeding, History of intracranial hemorrhage and Severe hepatic impairment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI. | Two weeks | Patients platelet inhibition was analyzed based on the P2Y12 reaction units (PRU) as high on treatment platelet reactivity (HPR), defined as P2Y12 reaction units (PRU) ≥208 and appropriate platelet inhibition on (API), defined as P2Y12 reaction units (PRU) \<208 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Establish the Number of Participants in the High On-treatment Platelet Reactivity (HPR) on Clopidogrel Group Who Demonstrated Appropriate Platelet Inhibition (API) After Switching to Ticagrelor for Two Weeks. | Two weeks | This measure was obtained by the number of participants who demonstrated high on treatment platelet reactivity (PRU \> / = 208) on Clopidogrel, and the number of participants who also resulted in the Appropriate Platelet Inhibition (PRU \< 208) after switching to Ticagrelor for two weeks of uninterrupted therapy x 100% . |
| Establish the Number of Participants With Appropriate Platelet Inhibition on Clopidogrel Who Demonstrated Appropriate Platelet Inhibition After Switching to Ticagrelor for Two Weeks. | Two weeks | The measure was obtained from the number of participants in the Appropriate Platelet Inhibition (PRU \< 208) on Clopidogrel and who remained with Appropriate Platelet Inhibition after switching to Ticagrelor for two weeks of uninterrupted therapy x 100 |
| Evaluate the Correlation Between PRU and VASP-PRI in CLI Patients During Clopidogrel Versus Ticagrelor Antiplatelet Therapy. | Two weeks | Correlation between the P2Y12 Reaction Units (PRU) and the Vasodilator-Stimulated Phosphoprotein Assay-Platelet Reactivity Index (VASP-PRI) used to test the inhibition of platelet aggregation after two weeks of uninterrupted therapy with Clopidogrel versus Ticagrelor in CLI participants |
Countries
United States
Participant flow
Recruitment details
Patients with diagnosis of CLI (Rutherford class IV, V and VI) on continuous dual antiplatelet therapy with clopidogrel 75 mg and aspirin 81 mg daily for at least 14+2 days
Pre-assignment details
A total of 53 patients consented and enrolled the study. 3 patients were excluded from the study and did not complete the study; one developed a skin reaction after the first IP dose; the other two due to events unrelated to the study (Pneumonia and Rheumatoid arthritis pericarditis). 50 Patients completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Experimental All subjects will receive Ticagrelor.
Ticagrelor: All patients will be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and VASP platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose. | 50 |
| Experimental All subjects will receive Ticagrelor.
Ticagrelor: All patients will be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and VASP platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose. | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
Baseline characteristics
| Characteristic | Experimental |
|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 50 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 53 |
| other Total, other adverse events | 1 / 53 |
| serious Total, serious adverse events | 1 / 53 |
Outcome results
Primary
To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI.
Patients platelet inhibition was analyzed based on the P2Y12 reaction units (PRU) as high on treatment platelet reactivity (HPR), defined as P2Y12 reaction units (PRU) ≥208 and appropriate platelet inhibition on (API), defined as P2Y12 reaction units (PRU) \<208
Time frame: Two weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ticagrelor | To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI. | Ticagrelor 6+-1 hour after baseline | 63 P2Y12 reaction units (PRU) |
| Ticagrelor | To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI. | Clopidogrel Baseline | 173 P2Y12 reaction units (PRU) |
| Ticagrelor | To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI. | Clopidogrel 6+-1 hour after the baseline dose | 140 P2Y12 reaction units (PRU) |
| Ticagrelor | To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI. | Ticagrelor Baseline | 71 P2Y12 reaction units (PRU) |
Secondary
Establish the Number of Participants in the High On-treatment Platelet Reactivity (HPR) on Clopidogrel Group Who Demonstrated Appropriate Platelet Inhibition (API) After Switching to Ticagrelor for Two Weeks.
This measure was obtained by the number of participants who demonstrated high on treatment platelet reactivity (PRU \> / = 208) on Clopidogrel, and the number of participants who also resulted in the Appropriate Platelet Inhibition (PRU \< 208) after switching to Ticagrelor for two weeks of uninterrupted therapy x 100% .
Time frame: Two weeks
Population: Participants who demonstrated on the High Platelet Reactivity (HPR) on clopidogrel and had Appropriate Platelet Inhibition (API) on ticagrelor
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | Establish the Number of Participants in the High On-treatment Platelet Reactivity (HPR) on Clopidogrel Group Who Demonstrated Appropriate Platelet Inhibition (API) After Switching to Ticagrelor for Two Weeks. | 17 Participants |
Secondary
Establish the Number of Participants With Appropriate Platelet Inhibition on Clopidogrel Who Demonstrated Appropriate Platelet Inhibition After Switching to Ticagrelor for Two Weeks.
The measure was obtained from the number of participants in the Appropriate Platelet Inhibition (PRU \< 208) on Clopidogrel and who remained with Appropriate Platelet Inhibition after switching to Ticagrelor for two weeks of uninterrupted therapy x 100
Time frame: Two weeks
Population: Participants who demonstrated API on Clopidogrel and remained with API after switching to Ticagrelor
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ticagrelor | Establish the Number of Participants With Appropriate Platelet Inhibition on Clopidogrel Who Demonstrated Appropriate Platelet Inhibition After Switching to Ticagrelor for Two Weeks. | 32 Participants |
Secondary
Evaluate the Correlation Between PRU and VASP-PRI in CLI Patients During Clopidogrel Versus Ticagrelor Antiplatelet Therapy.
Correlation between the P2Y12 Reaction Units (PRU) and the Vasodilator-Stimulated Phosphoprotein Assay-Platelet Reactivity Index (VASP-PRI) used to test the inhibition of platelet aggregation after two weeks of uninterrupted therapy with Clopidogrel versus Ticagrelor in CLI participants
Time frame: Two weeks
Population: All participants were on Clopidogrel 75mg daily for at least two weeks and then switched to Ticagrelor 90mg twice daily for two weeks of uninterrupted therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ticagrelor | Evaluate the Correlation Between PRU and VASP-PRI in CLI Patients During Clopidogrel Versus Ticagrelor Antiplatelet Therapy. | Ticagrelor | 0.47 Correlation Coefficient |
| Ticagrelor | Evaluate the Correlation Between PRU and VASP-PRI in CLI Patients During Clopidogrel Versus Ticagrelor Antiplatelet Therapy. | Overall Group | 0.6 Correlation Coefficient |
| Ticagrelor | Evaluate the Correlation Between PRU and VASP-PRI in CLI Patients During Clopidogrel Versus Ticagrelor Antiplatelet Therapy. | Clopidogrel | 0.73 Correlation Coefficient |