Protection of the Heart With Doxycycline During Coronary Artery Bypass Grafting

Cardiopulmonary Bypass Clinical Trial

Official title:

Protection of the Heart With Doxycycline During Coronary Artery Bypass Grafting: A Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00246740
• Other study ID #: Protect Study Protocol
• Status: Completed
• Phase: Phase 2
• First received: October 28, 2005
• Last updated: May 9, 2017
• Start date: October 2005
• Est. completion date: May 2009

Study information

• Verified date: May 2017
• Source: University of Alberta
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: May 2009
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiopulmonary Bypass
• Coronary Artery Bypass Grafting
• Reperfusion Injury

Intervention

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

Locations

Country	Name	City	State
Canada	University of Alberta Hospital	Edmonton	Alberta

Sponsors (1)

Lead Sponsor	Collaborator
University of Alberta

Country where clinical trial is conducted

Canada, 

References & Publications (1)

Schulze CJ, Castro MM, Kandasamy AD, Cena J, Bryden C, Wang SH, Koshal A, Tsuyuki RT, Finegan BA, Schulz R. Doxycycline reduces cardiac matrix metalloproteinase-2 activity but does not ameliorate myocardial dysfunction during reperfusion in coronary arter — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Left Ventricular Stroke Work Index (LVSWI)	Measure of global left ventricular function. The formula used for calculation is: LVSWI= SI x MAP x 0.0144 LVSWI = Left Ventricular Stroke Work Index (g*m/m2) SI = Stroke Index (mL/beat/m2) MAP = Mean Arterial Pressure (mmHg) 0.0144 is a conversion term to equalize units.	Before surgery up to 24h of reperfusion
Secondary	Cardiac Matrix Metalloproteinase-9 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion	Biochemical activity of MMP-9 activity in right atrial biopsies, measured at 10 minutes of reperfusion after surgery. To determine MMP-9 activity, 20 µg of total protein from both myocardial extracts and plasma were analyzed by gelatin zymography. For detailed methodology consult Cheung PY, Sawicki G, Wozniak M, et al: Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 2000; 101:1833-1839	Before surgery and 10 minutes reperfusion after surgery
Secondary	Cardiac Matrix Metalloproteinase-2 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion	Biochemical activity of MMP-2 activity in right atrial biopsies, measured at 10 minutes of reperfusion after surgery.	Before surgery and 10 minutes reperfusion after surgery
Secondary	Venous Plasma Cardiac Matrix Metalloproteinase-9 Activity Before and After Reperfusion	Biochemical activity of MMP-9 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery.	Before surgery and up to 72 h reperfusion after surgery
Secondary	Venous Plasma Cardiac Matrix Metalloproteinase-2 Activity Before and After Reperfusion	Biochemical activity of MMP-2 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery.	Before surgery and up to 72 h reperfusion after surgery
Secondary	Venous Plasma Concentration of Troponin-I	Measurement of levels of TnI (troponin-I), a marker of cardiac cell damage	Before surgery and 10 minutes reperfusion after surgery
Secondary	Cleaved TroponinI/GAPDH Ratios in Right Atrial Biopsy	Measurement of the ratios of cleaved TnI (troponin-I) versus GAPDH in biopsies collected from right atria. Measure is the ratio TnI/GAPDH	Before surgery and 10 minutes reperfusion after surgery
Secondary	Venous Plasma Concentration of C-reactive Protein	Measurement of inflammation marker C-reactive protein in plasma	Before surgery and up to 72 h reperfusion after surgery
Secondary	Venous Plasma Concentration of IL-6	Measurement of inflammation marker interleukin-6 in plasma	Before surgery and up to 72 h reperfusion after surgery

External Links

•   DOI of published results paper