Custodiol-HTK (Histidine-tryptophan-ketoglutarate) Solution as a Cardioplegic Agent

Coronary Artery Disease Clinical Trial

Official title:

Custodiol-HTK Solution as a Cardioplegic Agent- A Prospective Non-Inferiority Randomized Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01681095
• Other study ID #: 2012-125
• Status: Completed
• Phase: Phase 2
• Start date: August 2012
• Est. completion date: April 2016

Study information

• Verified date: January 2017
• Source: William Beaumont Hospitals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to demonstrate that Custodiol-HTK is not inferior to cold cardioplegic solution in patients undergoing cardiovascular surgery requiring cardioplegic arrest.

Description:

The objective of this study is to demonstrate that Custodiol is not inferior to cold cardioplegic solution for myocardial protection by comparing standard cold blood cardioplegia to Custodiol solution with respect to myocardial injury as measured by Creatine phosphokinase MB isoenzyme (CK-MB),troponin-I at 7 hours post surgery and changes in ejection fraction by trans-thoracic echocardiogram (TTE)or trans-esophageal echocardiogram (TEE) at 24 hours post surgery.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: April 2016
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients undergoing scheduled cardiac surgery requiring cardioplegic arrest with expected cross clamp time>45 minutes

• Patients age 18 and older

Exclusion Criteria:

• Pregnant women*

• Urgent or emergent cases

• Repeat cardiovascular surgical procedures

• Patients on dialysis

• Any known allergies to components of either cardioplegia solution *All women of child bearing potential must have a negative serum or urine pregnancy test.

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Heart Diseases
• Heart Valve Diseases
• Ischemia
• Myocardial Ischemia
• Valvular Heart Disease

Intervention

Drug:
• Custodiol HTK
After cross-clamping of the aorta approximately 1-2 L of Custodiol-HTK was infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml were administered as needed. The cardioplegic solution was delivered at a temperature of 4°C - 10°C.
• Cold Blood Cardioplegia
After cross-clamping the aorta, at least 1000 mL of a 4:1 mixture of cold blood: cold crystalloid was administered at a pressure of 300 mmHg or less via a twin roller pump. Every 20 minutes an additional > 200 mL was administered in an antegrade/retrograde fashion throughout the remainder of the case. The cardioplegic solution was delivered at a temperature of 4°C - 8°C.

Locations

Country	Name	City	State
United States	William Beaumont Hospital	Royal Oak	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Marc Sakwa, MD	Essential Pharmaceuticals, LLC

Country where clinical trial is conducted

United States, 

References & Publications (21)

Aarsaether E, Stenberg TA, Jakobsen Ø, Busund R. Mechanoenergetic function and troponin T release following cardioplegic arrest induced by St Thomas' and histidine-tryptophan-ketoglutarate cardioplegia--an experimental comparative study in pigs. Interact Cardiovasc Thorac Surg. 2009 Oct;9(4):635-9. doi: 10.1510/icvts.2009.208231. Epub 2009 Jul 23. — View Citation

Allen BS, Winkelmann JW, Hanafy H, Hartz RS, Bolling KS, Ham J, Feinstein S. Retrograde cardioplegia does not adequately perfuse the right ventricle. J Thorac Cardiovasc Surg. 1995 Jun;109(6):1116-24; discussion 1124-6. — View Citation

Arslan A, Sezgin A, Gultekin B, Ozkan S, Akay T, Uguz E, Tasdelen A, Aslamaci S. Low-dose histidine-tryptophan-ketoglutarate solution for myocardial protection. Transplant Proc. 2005 Sep;37(7):3219-22. — View Citation

Asano H, Kyo S, Ogiwara M, Tsunemoto M, Yokote Y, Omoto R, Koike K, Kobayashi T, Kobayashi J, Taketazu M. [Single-dose and high-volume Bretschneider cardioplegic solution for congenital heart surgery]. Kyobu Geka. 1999 Jan;52(1):82-6. Japanese. — View Citation

Athanasuleas C., Buckberg G. Myocardial protection and cardioplegia. Cardiopulmonary Bypass. New York: CambridgeUniversity Press; 2009: p. 82.

Beyersdorf F, Krause E, Sarai K, Sieber B, Deutschländer N, Zimmer G, Mainka L, Probst S, Zegelman M, Schneider W, et al. Clinical evaluation of hypothermic ventricular fibrillation, multi-dose blood cardioplegia, and single-dose Bretschneider cardioplegia in coronary surgery. Thorac Cardiovasc Surg. 1990 Feb;38(1):20-9. — View Citation

Bical OM, Fromes Y, Paumier D, Gaillard D, Foiret JC, Trivin F. Does warm antegrade intermittent blood cardioplegia really protect the heart during coronary surgery? Cardiovasc Surg. 2001 Apr;9(2):188-93. — View Citation

Braathen B, Jeppsson A, Scherstén H, Hagen OM, Vengen Ø, Rexius H, Lepore V, Tønnessen T. One single dose of histidine-tryptophan-ketoglutarate solution gives equally good myocardial protection in elective mitral valve surgery as repetitive cold blood cardioplegia: a prospective randomized study. J Thorac Cardiovasc Surg. 2011 Apr;141(4):995-1001. doi: 10.1016/j.jtcvs.2010.07.011. Epub 2010 Aug 30. — View Citation

Braathen B, Tønnessen T. Cold blood cardioplegia reduces the increase in cardiac enzyme levels compared with cold crystalloid cardioplegia in patients undergoing aortic valve replacement for isolated aortic stenosis. J Thorac Cardiovasc Surg. 2010 Apr;139(4):874-80. doi: 10.1016/j.jtcvs.2009.05.036. Epub 2009 Jul 26. — View Citation

Careaga G, Salazar D, Téllez S, Sánchez O, Borrayo G, Argüero R. Clinical impact of histidine-ketoglutarate-tryptophan (HTK) cardioplegic solution on the perioperative period in open heart surgery patients. Arch Med Res. 2001 Jul-Aug;32(4):296-9. — View Citation

Choi Y. S., Bang S. O. , Chang B. C. , Lee S. , Park C. H. , Kwak Y. L. A Comparison of the Effects of Histidine-tryptophan-ketoglutarate Solution versus Cold Blood Cardioplegic Solution on Myocardial Protection in Mitral Valve Surgery.Korean J Thorac Cardiovasc Surg. 2007;40(6):399-406

Fannelop T, Dahle GO, Salminen PR, Moen CA, Matre K, Mongstad A, Eliassen F, Segadal L, Grong K. Multidose cold oxygenated blood is superior to a single dose of Bretschneider HTK-cardioplegia in the pig. Ann Thorac Surg. 2009 Apr;87(4):1205-13. doi: 10.1016/j.athoracsur.2009.01.041. — View Citation

Gallandat Huet RC, Karliczek GF, van der Heide JN, Brenken U, Mooi B, van der Broeke JJ, Jenkins I, de Geus AF. Clinical effect of Bretschneider-HTK and St. Thomas cardioplegia on hemodynamic performance after bypass measured using an automatic datalogging database system. Thorac Cardiovasc Surg. 1988 Jun;36(3):151-6. — View Citation

Hachida M, Ookado A, Nonoyama M, Koyanagi H. Effect of HTK solution for myocardial preservation. J Cardiovasc Surg (Torino). 1996 Jun;37(3):269-74. — View Citation

Hendrikx M, Jiang H, Gutermann H, Toelsie J, Renard D, Briers A, Pauwels JL, Mees U. Release of cardiac troponin I in antegrade crystalloid versus cold blood cardioplegia. J Thorac Cardiovasc Surg. 1999 Sep;118(3):452-9. — View Citation

Kim S. , Lee Y. S. , Woo J. S. , Sung S. C. , Choi P. J. , Cho G. J., Bang J. H., Roh M. S. Histidine-tryptophan-ketoglutarate Versus Blood Cardioplegic Solutions: A Prospective, Myocardial Ultrastructural Study.Korean J Thorac Cardiovasc Surg. 2007;40(1):8-16.

Lee D. H., Park N. H., Keum D. Y., Choi S. Y., Lee K. S., Yoo Y. S. Comparison of Myocardial Protective Effect between the Cold Blood Cardioplegia and Histidine-Tryptophan-Ketoglutarate Solution.Korean J Thorac Cardiovasc Surg. 2004;37(9):739-41.

Sakata J, Morishita K, Ito T, Koshino T, Kazui T, Abe T. Comparison of clinical outcome between histidine-triptophan-ketoglutalate solution and cold blood cardioplegic solution in mitral valve replacement. J Card Surg. 1998 Jan;13(1):43-7. — View Citation

Savini C, Camurri N, Castelli A, Dell'Amore A, Pacini D, Suarez SM, Grillone G, Di Bartolomeo R. Myocardial protection using HTK solution in minimally invasive mitral valve surgery. Heart Surg Forum. 2005;8(1):E25-7. — View Citation

Schaper J, Scheld HH, Schmidt U, Hehrlein F. Ultrastructural study comparing the efficacy of five different methods of intraoperative myocardial protection in the human heart. J Thorac Cardiovasc Surg. 1986 Jul;92(1):47-55. — View Citation

Yang Q, He GW. Effect of cardioplegic and organ preservation solutions and their components on coronary endothelium-derived relaxing factors. Ann Thorac Surg. 2005 Aug;80(2):757-67. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB)	Creatine phosphokinase MB isoenzyme (CK-MB) difference from baseline 7 hours post surgery	Baseline and 7 hours post surgery
Primary	Change in Troponin I	Troponin I values, difference from baseline 7 hours post surgery	Baseline and 7 hours post surgery
Primary	Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE)	LV ejection fraction by TTE, difference from baseline at 24 hours post surgery	Baseline and 24 hours post surgery
Secondary	Cardiac Dysrhythmias	Number of participants with new or worsening of cardiac dysrhythmias	up to 36 hrs post surgery
Secondary	All Cause Mortality	Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative	30 days post procedure
Secondary	Cardiovascular Mortality	Number of participants with cardiovascular-related mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative	30 days post procedure
Secondary	Time on Mechanically Assisted Ventilation	time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit.	up to 36 hours post procedure
Secondary	Duration of Vasopressor / Inotropic Agent	Total time in minutes on any vasopressor or inotropic agent, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine	up to 36 hours post procedure
Secondary	Postoperative Inotropic Infusion >20 Minutes	Number of patients receiving vasopressor or inotropic infusion for greater than 20 minutes in the operating room, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine.	during operative procedure
Secondary	Intensive Care Unit (ICU) Length of Stay	Duration of stay in ICU, from ICU admission to ICU discharge	up to 100 days after admission
Secondary	Myocardial Infarction	Number or participants fulfilling at least two of the following 3 criteria: (1) CK-MB of 100 ug/L or more and/or troponin-I of 3.0 ug/L or more, (2) appearance of new postoperative Q waves on the EKG of more than 0.03 seconds, and (3) a new hypokinetic or akinetic area in the left or right ventricle by echocardiography.	up to 36 hours post procedure
Secondary	Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)	CK-MB measured pre-operatively	pre-operative
Secondary	Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)	CK-MB measured 24 hours post-operatively	24 hours post procedure
Secondary	Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)	CK-MB measured 48 hours post-operatively	48 hours post procedure
Secondary	Cardiac Marker - Troponin-I	Troponin-I measured pre-operatively	pre-operatively
Secondary	Cardiac Marker - Troponin-I	Troponin-I measured 24 hours post-operative	24 hours post procedure
Secondary	Cardiac Marker - Troponin-I	Troponin-I measured 48 hours post-operative	48 hours post procedure