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| [ Print-friendly version ] |
| The pharmacogenetics of aspirin resistance |
| ISRCTN | ISRCTN71079188 |
| ClinicalTrials.gov identifier | |
| Public title | The pharmacogenetics of aspirin resistance |
| Scientific title | |
| Acronym | N/A |
| Serial number at source | RGHT000270 |
| Study hypothesis |
The Antiplatelet Trialists' Collaboration meta-analyses (1994) documented a 25% reduction of death, myocardial infarction, and stroke in high-risk patients treated with aspirin. However, some patients continue to experience clinical events despite aspirin therapy, indicating that the anti-platelet effect of aspirin may not be uniform in all patients. Clinical aspirin resistance refers to those patients who have recurrent thrombotic events despite compliance with therapy. Biochemical aspirin refers to inadequate platelet inhibition on formal testing.
The aims of this proposed study are to use a repeated period crossover trial design in order to assess the reproducibility of aspirin resistance in healthy control individuals, using standard optical platelet aggregometry. Additional measures of platelet function will also be assessed using the Platelet Function Analyser (PFA-100) system, and levels of serum thromboxane B2 and urinary 11-dehydro thromboxane B2. Furthermore, the contribution of genetic polymorphisms in candidate genes to the phenomenon of aspirin resistance will be characterised. Polymorphisms of several contributing genes including the Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), GlycoProtein IIIa (GPIIIA), and adenosine 5-diphosphate receptor genes will be investigated using standard molecular approaches. |
| Ethics approval | Approval received from the Office for Research Ethics Committees Northern Ireland (ORECNI) on the 14th June 2006 (reference number: 06/NIR01/44). |
| Study design | Randomised repeated period crossover trial design |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Aspirin resistance |
| Participants - inclusion criteria | Healthy individuals aged between 18 to 60 years |
| Participants - exclusion criteria |
1. Use of other anti-platelet drugs (thienopyridines, GPIIb/IIIa antagonists, dipyridamole) because these drugs would interfere with platelet function assays
2. Use of other non-steroidal anti-inflammatory drugs, because of the pharmacodynamic interactions 3. History of dyspepsia or peptic ulceration requiring treatment with proton pump inhibitors/H2 antagonists, in view of the increased risk of gastrointestinal haemorrhage 4. History of systemic inflammatory diseases, in view of the need for these patients to take anti-inflammatory drugs 5. History of asthma 6. Use of other aspirin-containing medications (including herbal preparations) 7. Family or personal history of bleeding disorders 8. Use of oral anticoagulants 9. Platelet count outside the normal range (150,000 to 450,000/ml) 10. Significant anaemia (Haemoglobin [Hb] less than 10 g/dl) 11. Recent major surgery 12. Known significant malignant disease 13. known aspirin allergy 14. Pregnancy/women of childbearing potential 15. History of lactose intolerance, as lactose if the primary substance contained in the placebo 16. History of gout, as aspirin can precipitate gout 17. History of severe renal or hepatic dysfunction 18. Planned surgery during participation in trial 19. Excessive alcohol ingestion (more than 40 units per week) 20. Inability to provide informed consent |
| Anticipated start date | 01/08/2006 |
| Anticipated end date | 01/08/2009 |
| Status of trial | Completed |
| Patient information material | |
| Target number of participants | 150 |
| Interventions |
The study is a repeated crossover trial design of two treatments and four periods. The aspirin dose will be either 75 mg or 300 mg but will be fixed within individual patients. A subject will be randomised to one of four treatment sequences: ABBA, BAAB, ABAB or BABA, where A is active drug and B is placebo.
Each individual study period will last for three weeks, therefore the total period of study for each patient will be 12 weeks. This type of design allows the study of treatment, subject, period and carry-over effects, and their interactions, specifically the subject-by-treatment interaction. The individuals will be seen at baseline and once informed consent has been obtained, baseline tests for platelet function tests (optical aggregometry, PFA-100) and serum/urine thromboxane levels will be taken, as will whole blood for later analysis of genetic polymorphisms. Further samples for platelet function testing will be taken at the end of each crossover period. |
| Primary outcome measure(s) |
1. Assess the reproducibility of aspirin resistance in healthy control individuals, as defined by standard optical platelet aggregometry
2. Characterise the contribution of genetic polymorphisms in candidate genes, specifically the cyclooxygenase and adenosine 5-diphosphate receptor genes, to the phenomenon of aspirin resistance |
| Secondary outcome measure(s) |
1. The assessment of the reproducibility of aspirin response as defined by other platelet function tests (PFA-100 system, thromboxane levels)
2. The contribution of other genetic polymorphisms to the phenomenon of aspirin resistance 3. The correlation between the various platelet function tests used in this study |
| Sources of funding |
1. Royal Hospitals Trust Clinical Fellowship (UK)
2. Northern Ireland Chest Heart & Stroke Association (UK) |
| Trial website | |
| Publications | |
| Contact name | Dr Pascal McKeown |
| Address |
Consultant/Senior Lecture in Cardiology
Royal Hospitals Trust West Wing, First Floor Grosvenor Road |
| City/town | Belfast |
| Zip/Postcode | BT12 6BA |
| Country | United Kingdom |
| p.p.mckeown@qub.ac.uk | |
| Sponsor | Royal Group of Hospitals Trust (UK) |
| Address |
Royal Research Office
First Floor Education Centre Royal Victoria Hospital Grosvenor Road |
| City/town | Belfast |
| Zip/Postcode | BT12 6BA |
| Country | United Kingdom |
| Tel | +44 (0)28 9063 5372 |
| Fax | +44 (0)28 9063 4812 |
| i.young@qub.ac.uk | |
| Sponsor website: | http://www.royalhospitals.org/ |
| Date applied | 06/10/2006 |
| Last edited | 14/03/2007 |
| Date ISRCTN assigned | 14/03/2007 |
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| © 2010 ISRCTN unless otherwise stated. | |
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