Multiple Daily Doses Of Aspirin To Overcome Aspirin Hyporesponsiveness Post Cardiac Bypass Surgery (ASACABG)

• ClinicalTrials.gov Identifier: NCT01618006
• Recruitment Status: Completed
• First Posted: June 13, 2012
• Last Update Posted: March 19, 2015
• Sponsor: Hamilton Health Sciences Corporation
• Information provided by (Responsible Party): Jeremy Paikin, Hamilton Health Sciences Corporation

Study Description

Brief Summary:

Cardiac bypass surgery is an important treatment for patients with severely blocked arteries (tubes that delivery oxygen and nutrients to the heart). Hundreds of thousands of these operations are done each year to help relieve patients' chest pain and to prevent future heart attacks. The surgery is done by "bypassing" blood flow around badly clogged arteries by sewing on healthy vessels from another part of the body (usually from the leg or the chest). Aspirin (a blood thinner) is given to patients once a day after their surgery because it stops "sticky" cells in the blood (platelets) from blocking these new vessels (which may lead to a future heart attack).

Research has shown that aspirin does not work as well in people after they have bypass surgery as the investigators might expect (for reasons that are not fully understood). One reason aspirin may not work as well after surgery is because the body makes many more platelets after surgery than it would under normal circumstances. All of these new platelets overwhelm the aspirin and continue to be "sticky" and ready to block off arteries. The investigators believe that giving multiple daily doses of aspirin following bypass surgery is more effective than giving aspirin once daily at blocking platelet activity.

Condition or disease	Intervention/treatment	Phase
Postoperative; Dysfunction Following Cardiac Surgery	Drug: Aspirin	Phase 2

Detailed Description:

Background:

Cardiovascular disease caused by athero-thrombosis is the number one cause of long-term morbidity and death worldwide. Many patients with advanced coronary disease benefit from Coronary Artery Bypass Graft (CABG) by improving symptoms and increasing their longevity.

However, the benefits of CABG surgery are attenuated by early graft failure. The administration of aspirin in the post-operative period has been shown in randomized controlled trials (RCT) to reduce the risk of graft occlusion, although rates remain unacceptably high. Patients undergoing CABG surgery transiently develop aspirin resistance, which likely contributes to vein graft failure.

The investigators believe the aspirin resistance is a consequence of rapid platelet turnover in the early postoperative period, resulting in a large number of platelets unexposed to aspirin (due to its short half life). The investigators hypothesize that by increasing the frequency of aspirin dosing, the investigators can reverse the aspirin resistance encountered post CABG surgery. The investigators are proposing a RCT comparing two different doses of aspirin (81mg and 325mg daily) to 81mg qid to determine whether multiple daily dosing can overcome aspirin resistance.

(1)Given that platelet production is increased many-fold after CABG surgery (and the short half-life of aspirin), the investigators hypothesize that increasing the frequency of aspirin dosing will lead to the acetylation of a greater number of platelets over the course of the day leading to an improved antiplatelet effect (as measured by serum thromboxane and platelet aggregation assays); (2) The investigators will examine three platelet-related single nucleotide polymorphisms (SNP) that have been implicated in aspirin hyporesponsiveness.

The investigators are proposing a single centre, randomized, open-label, RCT in 60 patients undergoing elective or urgent CABG surgery, to receive ASA 81mg daily, 325mg daily or 81 mg qid starting day 1 post-operatively. All patients will receive 325mg 6hrs following the procedure (day of operation) as long as there is no contraindication for antiplatelet therapy (ie significant bleeding) - as per the investigators centre's standard clinical practice. Further details on aspirin administration and outcome measurements are reported below.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multiple Daily Doses Of Aspirin To Overcome Aspirin Hyporesponsiveness Post Cardiac Bypass Surgery
• Study Start Date: January 2012
• Actual Primary Completion Date: April 2013
• Actual Study Completion Date: August 2013

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Aspirin 81mg daily; Patients will receive 81mg daily during the postoperative period.	Drug: Aspirin; Aspirin 81mg po daily x 7days or end of hospitalization. First dose administered on post op day 1.
Active Comparator: Aspirin 325mg daily; Patients will receive 325mg daily during the postoperative period, until day 7 postop or the end of hospitalization.	Drug: Aspirin; Aspirin 325mg po daily x 7days or end of hospitalization. First dose administered on post op day 1.
Experimental: Aspirin 81mg four times daily; Patients will receive ASA 81mg four times daily until postoperative day 7 or end of hospitalization	Drug: Aspirin; Aspirin 81mg po four times daily x 7days or end of hospitalization. First dose administered on post op day 1.

Outcome Measures

Primary Outcome Measures :

1. Serum Thromboxane: Define an inadequate aspirin response as a value >0.69 ng/ml, which is 2 SD above the mean of aspirin-treated patients [ Time Frame: Postoperative Day 4 ]

Secondary Outcome Measures :

1. Arachidonic Acid Induced Light Transmission Aggregometry (LTA): Aggregation will be expressed as the maximum percent change in light transmittance from baseline, with platelet-poor plasma used as a reference. [ Time Frame: Postoperative Day 4 ]
2. Arachidonic Acid Induced Multiple Electrode Platelet Aggregometry (MEA):Aggregation was recorded for 6 minutes and will be reported as the area under the curve (aggregation units x min). [ Time Frame: Postoperative Day 4 ]
3. DNA genetic analyses for single nucleotide polymorphisms [ Time Frame: A single preoperative blood sample was drawn (on average of 1 week prior to surgery) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Adult subjects who undergo elective or urgent CABG surgery who are on or off aspirin during the preoperative period

Exclusion Criteria:

• (a) initial platelet count <100,000 (b) significant liver disease (c) renal impairment (CrCl<30 ml/min/1.73 m2) (d) receiving (or planned) clopidogrel therapy (e) receiving NSAIDs or other drugs that might interfere with aspirin's platelet-inhibitory effect (f) need for therapeutic doses of parenteral or oral anticoagulants after surgery and (g) off-pump CABG (h) clinically important bleeding (chest tube drainage >200ml/hr for 6hrs)

Contacts and Locations

Locations

Canada, Ontario

Hamilton General Hospital

Hamilton, Ontario, Canada, L8L2X2

Sponsors and Collaborators

Hamilton Health Sciences Corporation

Investigators

• Principal Investigator: Jeremy Paikin, MD; Cardiology Fellow
• Principal Investigator: John Eikelboom, MBBS; Hematologist, PHRI researcher
• Principal Investigator: Richard Whitlock, MD; Cardiac Surgeon, PHRI researcher
• Principal Investigator: Guillaume Pare, MD; Medical Biochemist, PHRI researcher
• Study Chair: Jack Hirsh, MD; Hematologist, Professor Emeritus, PHRI researcher

More Information

• Responsible Party: Jeremy Paikin, Principal Investigator, Hamilton Health Sciences Corporation
• ClinicalTrials.gov Identifier: NCT01618006
• Other Study ID Numbers: NIF-11271
• First Posted: June 13, 2012
• Last Update Posted: March 19, 2015
• Last Verified: March 2015

Additional relevant MeSH terms:

Aspirin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics