PLATE NOX: Is Efficacy of PLAtelet Aggregation Inhibition by Ticagrelor Mediated P2Y12 Blockade Dependent Upon Endogenous Endothelial Nitric OXide?

Sponsor

Hull University Teaching Hospitals NHS Trust (Other)

Overall Status

Completed

CT.gov ID

NCT02169596

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

5.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background

Acute coronary syndrome (ACS) is a term representing all diseases related to reduction in blood flow to the heart characterised by clot formation over a segment of blood vessel narrowing. A major constituent of clot are blood cells called platelets and many of the medications used in ACS target platelet function. Ticagrelor is known to reduce platelet activity in clot formation by blocking a specific step in the process (P2Y12 receptors). A recent study has found that the presence of ticagrelor may also reduce clot formation by significantly enhancing another process involving the molecule nitric oxide (NO). This is of particular interest if translates into clinical practice, as many patients with heart disease have abnormal function of their blood vessel lining. This is known to cause a reduction in available nitric oxide. Does this therefore mean these patients will have a reduced response to ticagrelor therapy and subsequently be at increased risk of clot formation?

Aims

Will ticagrelor increase the anti clot effect of vessel lining produced nitric oxide?
Do patients with diabetes or smokers, who have poor function of their vessel lining, have a reduced response to ticagrelor?

Methods

This is a pilot study in which we propose to look at 64 patients with known disease of their heart blood vessels, with an equal mix of smokers, diabetics, smoking diabetics and non smoking non diabetics. We will also recruit ten healthy normal subjects to ensure that our tests produce the same results as the basic science study mentioned above.

To answer the questions posed we will perform blood tests, primarily looking at platelet function, and non-invasive blood vessel lining assessment. This will be done before and after ticagrelor treatment on each participant, enabling statistical comparison.

Condition or Disease	Intervention/Treatment	Phase
Acute Coronary Syndome	Drug: Ticagrelor Other: EndoPAT - endothelial assessment	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

74 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

a Single Centre Open Pilot Study to Explore if the Efficacy of PLAtelet Aggregation Inhibition by Ticagrelor Mediated P2Y12 Blockade Dependent Upon Endogenous Endothelial Nitric OXide?

Study Start Date :

Jun 1, 2015

Actual Primary Completion Date :

Jul 1, 2016

Actual Study Completion Date :

Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: Coronary Artery Disease Blood tests to assess platelet function and EndoPAT assessment for endothelial function testing before and after ticagrelor administration (90mg BD)	Drug: Ticagrelor Blood tests taken for flow cytometry Other Names: blood test Other: EndoPAT - endothelial assessment
Other: Healthy Normals Blood tests to assess platelet function and EndoPAT assessment for endothelial function testing before and after ticagrelor administration (90mg BD)	Drug: Ticagrelor Blood tests taken for flow cytometry Other Names: blood test Other: EndoPAT - endothelial assessment

Arm

Intervention/Treatment

Other: Coronary Artery Disease

Blood tests to assess platelet function and EndoPAT assessment for endothelial function testing before and after ticagrelor administration (90mg BD)

Drug: Ticagrelor

Blood tests taken for flow cytometry

Other Names:

blood test

Other: EndoPAT - endothelial assessment

Other: Healthy Normals

Blood tests to assess platelet function and EndoPAT assessment for endothelial function testing before and after ticagrelor administration (90mg BD)

Drug: Ticagrelor

Blood tests taken for flow cytometry

Other Names:

blood test

Other: EndoPAT - endothelial assessment

Outcome Measures

Primary Outcome Measures

Platelet Function [up to 12 months (completion of study)]
Direct testing with flow cytometry measuring fibrinogen binding, P-selectin, CD40L expression

Secondary Outcome Measures

Reactive Hyperaemia Index [at 1 month, 6 months and at 12 months (completion of study)]
EndoPAT endothelial assessment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Age > 18 years
Coronary artery disease deemed to require Percutaneous Coronary Intervention
Diabetics must be established on oral or subcutaneous therapy
Non diabetics must have HbA1c levels between 20-42 mmol/mol
Current smokers are those that have smoked greater than 100 cigarettes and currently smoke on a daily basis
Non smokers have not smoked for greater than 3 years (and not on nicotine replacement)
Healthy controls are non smokers without medical history and taking no regular medication

Exclusion Criteria:

Contra-indication to dual antiplatelet therapy
Known bleeding disorders
Known malignant disease
Known myeloproliferative disease/malignant paraproteinaemia/heparin induced thrombocytopenia
Previous intracranial bleed
Already established on dual antiplatelet therapy
Known moderate-severe liver or splenic failure
Severe renal impairment
Major surgery due within one month of enrolment or before completion of measurements
Known allergy/intolerance to aspirin or ticagrelor
Reaction or side effect of aspirin or ticagrelor resulting in discontinuation prior to completion
Known allergy/intolerance to 3-hydroxy-3-methylglutaric acid Coenzyme A reductase inhibitor therapy (statins)
Concurrent use of high dose simvastatin/lovastatin (>40mg daily)
Currently taking medication that will interact with platelet function ie NSAIDS, antibiotics or herbal remedies
Concurrent use of strong cytochrome P450 3A4 inhibitors eg. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir
Concurrent use of strong cytochrome P450 3A4 inducers e.g. rifampicin, dexamethasone, phenytoin, carbamazepine and phenobarbital
Known sick sinus syndrome, second or third degree AV block or bradycardia-related syncope without permanent pacemaker in situ
Known severe asthma/Chronic Obstructive Pulmonary Disease or worsening of dyspnoeic symptoms on ticagrelor
Known severe gout
Currently taking calcium channel antagonist
Currently taking long acting nitrate
Currently taking >15mg/week of methotrexate
Women pregnant, breast feeding or of child bearing potential
Require anticoagulation on warfarin or Novel Oral AntiCoagulant
Platelet count <150 x109/L or >400 x109/L
Known blood bourne virus carrier
Unable to give informed consent
Involvement in a conflicting study
Non English speaker

Withdrawal Criteria following initial recruitment due to not meeting inclusion or exclusion criteria

Develop significant bleeding complications of medication requiring discontinuation of antiplatelet therapy prior to completion of the study
Urgent surgery undertaken during the study resulting in discontinuation of antiplatelet therapy prior to completion of the study
React or develop side effects of aspirin or ticagrelor resulting in discontinuation prior to completion of the study
Commence medication that will interact with platelet function before completion of the study
Commence use of strong cytochrome P450 3A4 inhibitors before completion of the study
Commence use of strong cytochrome P450 3A4 inducers before completion of the study
Worsening of dyspnoea in subjects with mild/moderate asthma/Chronic Obstructive Pulmonary Disease resulting in discontinuation of ticagrelor prior to completion of the study
Platelet count on initial sampling <150 x109/L or >400 x109/L
Non diabetic patients HbA1c level >42 mmol/mol
Noncompliance with medication
Subject wishes to no longer participate in the study (no reason or time period required)