Official Title: “Protection of the Heart With Doxycycline During Coronary Artery Bypass Grafting: A Pilot Study”

The purpose of this study is to determine whether doxycycline(Periostat)at a sub-antimicrobial dose will decrease reperfusion injury after coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB).

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment

Study Primary Completion Date: May 2008

This proposal is for a randomized, placebo-controlled, double-blinded study of the use of doxycycline in patients requiring CABG surgery. Patients will be randomized 1:1 to receive either doxycycline or placebo.

This study will be conducted in a blinded manner. The pharmacy will randomize patients and will have the randomization code. The code will only be broken in the case of an emergency and the event will be fully documented.

In addition to standard care, patients will receive oral administration of 20 mg of doxycycline or placebo twice a day at least 2 days prior to surgery, on the day of surgery, and on postoperative days 1, 2, and 3.

Myocardial atrial biopsies will be taken at 2 time points during the CABG procedure: during cannulation of the right atrium and 10 minutes after cross-clamp release. Tissue will be analyzed for MMP-2 and -9 activity and TnI and MLC-1 levels.

A Swan-Ganz-Catheter will be placed in the pulmonary artery over 24 hours to measure hemodynamics (LVSWI).

A coronary sinus catheter will be placed under echocardiographic guidance prior to initiation of CPB (will be removed 20 minutes after cross-clamp release).

Patients will have an additional ECG on post-operative days 1 and 3.

Additional blood will be drawn to determine doxycycline plasma levels, MMP-2 and -9 activity, total gelatinolytic activity, and levels of troponin I and T products at the following time points: pre-induction, prior to initiation of CPB, 10 and 20 minutes following the release of the aortic cross clamp (arterial and venous) and 3, 6, 24 and 72 hours post aortic cross clamp removal (venous). Each of the above samples will require 6 mL of blood for a study total of 72 mL. At the time of each blood draw we will measure and record the hematocrit value.

Intervention(s) in this Clinical Trial

• Drug: Periostat
  • In addition to standard care, patients will receive oral administration of 20 mg of doxycycline or placebo twice a day at least 2 days prior to surgery, on the day of surgery, and on postoperative days 1, 2, and 3.

Primary Measures

• Doxycycline, a tetracycline antibiotic that also possesses secondary inhibitory effects on matrix metalloproteinases (MMPs), will attenuate myocardial and systemic activation of MMPs if administered to patients prior to the onset of CPB.
  • Time Frame: 2 days prior to surgery until 3 days post operative
    Safety Issue?: No

Secondary Measures

• Attenuating the activation of MMPs will reduce cleavage of contractile protein regulatory elements such as troponin I (TnI) and myosin light chain 1 (MLC-1), which will improve cardiac functional recovery after CPB.
  • Time Frame: 2 days prior to surgery until 3 days post operative
    Safety Issue?: No

Inclusion Criteria:

• Written informed consent
• Aged 18 through 80 years, inclusive
• Scheduled for primary CABG surgery with CPB

Exclusion Criteria:

• Females of childbearing potential
• Emergency CABG
• Previous sternotomy
• Planned simultaneous surgery (i.e. valve repair or carotid endarterectomy)
• Myocardial infarction within 48 hours
• Pre-operative atrial fibrillation
• Pre-operative ventricular pacing or left bundle branch block (LBBB)
• Known hypersensitivity to tetracycline class antibiotics
• Renal failure requiring dialysis

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Alberta

Overall Clinical Trial Officials and Contacts

Barry A Finegan, MB, FFARS(I), FRCPC Principal Investigator Department of Anesthesiology and Pain Medicine, University of Alberta Hospital  

Information obtained from ClinicalTrials.gov on December 03, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00246740

Study ID Number: Protect Study Protocol

ClinicalTrials.gov Identifier: NCT00246740

Health Authority: Canada: Health Canada