Clinical trial NCT01618006: Multiple Daily Doses Of Aspirin To Overcome Aspirin Hyporesponsiveness Post Cardiac Bypass Surgery
Official title: Multiple Daily Doses Of Aspirin To Overcome Aspirin Hyporesponsiveness Post Cardiac Bypass Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Postoperative; Dysfunction Following Cardiac Surgery
Lead sponsor: Hamilton Health Sciences Corporation
Sponsor class: OTHER
First posted: 2012-06-13
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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)

Primary outcomes:
measure: 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
timeFrame: Postoperative Day 4
Secondary outcomes:
measure: 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.
timeFrame: Postoperative Day 4
measure: 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).
timeFrame: Postoperative Day 4
measure: DNA genetic analyses for single nucleotide polymorphisms
timeFrame: A single preoperative blood sample was drawn (on average of 1 week prior to surgery)
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
Study officials:
affiliation: Cardiology Fellow
name: Jeremy Paikin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hematologist, PHRI researcher
name: John Eikelboom, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiac Surgeon, PHRI researcher
name: Richard Whitlock, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Biochemist, PHRI researcher
name: Guillaume Pare, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hematologist, Professor Emeritus, PHRI researcher
name: Jack Hirsh, MD
role: STUDY_CHAIR
References: