The Effect of Ticagrelor on 15-Epi-Lipoxin A4 and Inflammation

Ticagrelor and clopidogrel are FDA-approved drugs for inhibition of platelet hyper-reactivity in certain clinical situations. The platelet inhibition and patient outcomes (PLATO) trial showed that in patients with acute coronary syndromes, ticagrelor significantly reduced the primary endpoint (cardiovascular death, myocardial infarction or stroke), all-cause mortality and cardiovascular mortality compared to clopidogrel. It has been suggested that in addition to its anti-platelet effects, ticagrelor has additional unique effects, including anti-inflammatory effects that are not shared by clopidogrel. In the present study the investigators will assess whether ticagrelor, as compared to clopidogrel, increases serum levels of 15-epi-lipoxin A4, a potent endogenous anti-inflammatory mediator.

Study Overview

• Status: Withdrawn
• Conditions: Atherosclerosis
• Intervention / Treatment: Drug: Clopidogrel; Drug: Ticagrelor

Detailed Description

Clopidogrel, ticagrelor and prasugrel are routinely used for platelet inhibition in addition to aspirin in patients after acute coronary syndromes. The platelet inhibition and patient outcomes (PLATO) trial showed that in patients with acute coronary syndromes, ticagrelor significantly reduced the primary endpoint (cardiovascular death, myocardial infarction or stroke), all-cause mortality and cardiovascular mortality compared to clopidogrel. On the other hand, when compared with clopidogrel in patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy did not affect overall mortality despite the fact that it was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. This may suggest that ticagrelor possesses additional (pleiotropic) effects besides platelet inhibition.

The investigators have recently shown that pioglitazone increases 15-epi-lipoxin A4 blood levels in patients. The investigators have recently found that in the rat, ticagrelor increases tissue levels of 15-epi-lipoxin A4 in the heart, aorta and kidney.

It is plausible that some of the favorable effects of ticagrelor seen in the clinical studies are mediated via the anti-inflammatory effects of 15-epi-lipoxin A4.

15-epi-lipoxin A4 is a potent anti-inflammatory and inflammation-resolving mediator derived from arachidonic acid. Several studies have suggested that ticagrelor has anti-inflammatory properties in various animal models. In the present study the investigators will assess if ticagrelor increases blood 15-epi-lipoxin A4 levels at doses used in patients.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Baylor Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Provision of informed consent prior to any study specific procedures

Women of childbearing potential must be using an acceptable method of contraception to avoid pregnancy throughout the study

Patients with stable coronary artery disease (3-12 months after Acute Coronary Syndrome) who receive clopidogrel for at least 3 months.

Exclusion Criteria:

Recent stroke or acute coronary syndromes (<3 months before randomization).

Concurrent use of aspirin >100 mg/day where the dose reduction to 81 mg/day is contraindicated.

Current use of theophylline.

Concurrent use of Non Steroidal Anti-Inflammatory Drugs.

Patients receiving the following medications: ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, telithromycin, rifampin, dexamethasone, phenytoin, carbamazepine, or phenobarbital. Patients receiving simvastatin or lovastatin at doses greater than 40 mg daily.

Patients with type 2 diabetes with a fasting plasma glucose greater than 200 mg/dl.

Active inflammatory disease or chronic infection.

Contraindication for aspirin, clopidogrel or ticagrelor.

Women who are pregnant or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Clopidogrel; Clopidogrel 75 mg once a day by mouth for 30 days	Drug: Clopidogrel; Clopidogrel 75 mg once a day by mouth for 30 days; Other Names: Plavix
Active Comparator: Ticagrelor; Ticagrelor 90 mg twice daily by mouth for 30 days	Drug: Ticagrelor; Ticagrelor 90 mg twice daily by mouth for 30 days; Other Names: Brilinta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma levels of 15-epi-lipoxin A4	Percent change in plasma levels of 15-epi-lipoxin A4 from baseline (%)	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma levels of C Reactive Protein (CRP)	Percent changes in plasma CRP from baseline (%)	30 days
platelet aggregation in blood sample	Percentage change in inhibition of platelet aggregation in blood sample from baseline (%)	30 days

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Investigators: Principal Investigator: Yochai Birnbaum, MD, Baylor College of Medicine, Houston

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Anticipated): January 1, 2018
• Study Completion (Anticipated): July 1, 2018

Study Registration Dates

• First Submitted: December 8, 2015
• First Submitted That Met QC Criteria: December 9, 2015
• First Posted (Estimate): December 10, 2015

Study Record Updates

• Last Update Posted (Actual): December 11, 2019
• Last Update Submitted That Met QC Criteria: December 9, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: atherosclerosis; inflammation; 15-epi-lipoxin A4
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Inflammation; Atherosclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel
• Other Study ID Numbers: H-33860

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO