Overcoming High On-Treatment Platelet Reactivity (HPR) During Prasugrel Therapy With Ticagrelor (HEIGHTEN)

Overcoming High On-Treatment Platelet Reactivity (HPR) During Prasugrel Therapy

The primary objective is to determine the pharmacodynamic effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable Coronary artery disease (CAD) patients who exhibit high-on prasugrel platelet reactivity defined as Vasodilator Stimulated Phosphoprotein-Phosphorylation (VASP-P) >50%.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Prasugrel; Drug: Ticagrelor

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kevin P Bliden, BS, MBA; Phone Number: 4106014795; Email: kbliden@lifebridgehealth.org

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Recruiting
      • Sinai Center for Thrombosis Research
      • Contact: Kevin P Bliden, B.S. MBA; Phone Number: 410-601-4795; Email: kbliden@lifebridgehealth.org
      • Contact: Tania B Gesheff, MSN; Phone Number: 4106014795; Email: tgesheff@lifebridgehealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female; age ≥ 18 and < 75 years
2. Weight ≥ 60 kg
3. Currently on ASA therapy and eligible to reduce ASA dose to 81 mg daily if on higher dosing
4. On stable prasugrel maintenance dose for ≥1 month
5. Stable CAD patients defined as: subjects with documented evidence of a history of atherosclerotic coronary artery disease/surgical revascularization (defined as either a prior myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft surgery). A minimum of 1 month must have elapsed between a subject's enrolment and any acute event, revascularization procedure or hospitalization for chest pain for that subject.
6. If female, may be enrolled if one of the following 3 criteria are met: 1)Had a hysterectomy or tubal ligation at least 6 months prior to signing ICF, 2)Post-menopausal for at least 1 year, 3)If of childbearing potential, will practice 1 of the following methods of birth control throughout the study: oral, injectable, or implantable hormonal contraceptives; intrauterine device; diaphragm plus spermicide; or female condom plus spermicide. Methods of contraception that are not acceptable are partner's use of condoms or partner's vasectomy.
7. Able and willing to provide written informed consent before entering the study

Exclusion Criteria:

1. Subject plans to undergo coronary revascularization at any time during the trial
2. Presence or history of any of the following: ischemic or hemorrhagic stroke; transient ischemic attack (TIA); intracranial neoplasm; arteriovenous malformation, or aneurysm; intracranial hemorrhage; head trauma (within 3 months of study entry)
3. History of refractory ventricular arrhythmias with an increased risk of bradycardic events (eg, subjects without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree atrioventricular (AV) block or bradycardic-related syncope)
4. History or evidence of congestive heart failure (New York Heart Association Class III or above ≤ 6 months before screening
5. Severe hepatic impairment defined as ALT> 2.5 X ULN
6. Uncontrolled hypertension, or systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at screening
7. Severely impaired renal function (glomerular filtration rate < 30 mL/minute) or on dialysis
8. Concomitant use with parenteral or oral anticoagulants
9. Platelet count <100 X103

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Non-HPR group; The non-HPR group will have PD and genetic testing, with no change in medication.
Active Comparator: HPR Group; This arm will be split into Group A and Group B which will receive Ticagrelor/Prasugrel in a crossover manner.	Drug: Prasugrel; Patients will discontinue ticagrelor treatment and start 10 mg prasugrel daily while continuing 81 mg of aspirin daily.; Drug: Ticagrelor; Patients will be given 180 mg of Ticagrelor followed by 90 mg twice a day while continuing 81 mg of aspirin daily).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic (PD) Vasodilator Stimulated Phosphoprotein-Phosphorylation(VASP-P) in High On Prasugrel Platelet Reactivity(HPPR) stable CAD patients	The primary objective is to determine the pharmacodynamic effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable CAD patients who exhibit high-on prasugrel platelet reactivity defined as VASP-P>50%.	2 hours, 4 hours, and 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of HPPR	Determine the prevalence of HPPR in a stable PCI population.	2 hours, 4 hours, and 14 days
CYP2C19 relation to occurence of HPPR	Determine the relation of CYP2C19 activity to the occurrence of HPPR.	2 hours, 4 hours, and 14 days
PD VerifyNow in HPPR stable CAD patients	Evaluate the PD effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable CAD patients who exhibit HPPR defined as PRU >208 by VerifyNow P2Y12	2 hour, 4 hour, 14 days
PD LTA in HPPR stable CAD patients	Evaluate the PD effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable CAD patients who exhibit HPPR based on light transmittance aggregometry (5 and 20 uM ADP, 4ug/mL Collagen)	2 hours, 4 hours, 14 days
Frequency of HPR	To determine the frequency of HPR after switching from ticagrelor to prasugrel after 14 days of treatment.	2 hours, 4 hours, and 14 days
PD effect(Prasugrel) relation to CYP2C19	To determine if the PD effect of prasugrel is related to the activity of CYP2C19 (phenotyping and genotyping) by measuring patients with and without HPPR.	2 hours, 4 hours, and 14 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events	To evaluate the safety and tolerability of switching subjects from Prasugrel to Ticagrelor and vice versa.	14 days, 28 days

Collaborators and Investigators

• Sponsor: LifeBridge Health
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Paul A Gurbel, MD, Lifebridge Health

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: May 28, 2013
• First Submitted That Met QC Criteria: May 30, 2013
• First Posted (Estimate): June 5, 2013

Study Record Updates

• Last Update Posted (Estimate): November 21, 2014
• Last Update Submitted That Met QC Criteria: November 20, 2014
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Coronary artery disease; anti-platelet medications; Platelet-aggregation Inhibitors
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; 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; Prasugrel Hydrochloride
• Other Study ID Numbers: 2015 (American Sleep Medicine Foundation); ISSBRIL0149 (Other Identifier: AstaZeneca)