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

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)