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

NCT01681095 | Completed Phase 2 Results DMC

• 1 other identifier: 2012-125
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Valvular Heart Disease

Keywords

Physiological Effects of Drugs; Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Mannitol; Cardiac Surgery; Cardioplegic Solutions; HTK solution; Myocardial protection; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases

Outcome Measures

Primary Outcomes (3)

• 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

• Change in Troponin I

  Troponin I values, difference from baseline 7 hours post surgery

  Baseline and 7 hours post surgery

• 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 Outcomes (14)

• Cardiac Dysrhythmias

  up to 36 hrs post surgery

• All Cause Mortality

  30 days post procedure

• Cardiovascular Mortality

  30 days post procedure

• Time on Mechanically Assisted Ventilation

  up to 36 hours post procedure

• Duration of Vasopressor / Inotropic Agent

  up to 36 hours post procedure

Study Arms (2)

Cardioplegia: Custodiol HTK Solution

EXPERIMENTAL

Custodiol HTK (histidine-tryptophan-ketoglutarate) cardioplegia: One liter of HTK solution (Custodiol; Koehler Chemi, Alsbach-Haenlien, Germany) contains the following components: 15 mmol/L sodium chloride, 9 mmol/L potassium chloride, 4 mmol/L magnesium chloride, 18 mmol/L histidine hydrochloride, 180 mmol/L histidine, 2 mmol/L tryptophan, 30 mmol/L mannitol, 0.015 mmol/L calcium chloride, 1 mmol/L potassium hydrogen 2-ketoglutarate, osmolarity 310 mOsm/kg, pH 7.02-7.20. Custodiol-HTK was delivered to establish and maintain cardiac arrest. 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. Custodiol-HTK was delivered at a temperature of 4°C - 10°C.

Drug: Custodiol HTK

Cold Blood Cardioplegia

ACTIVE COMPARATOR

Cold Blood Cardioplegia: One liter of cold blood cardioplegic solution, mixed at a ratio of 4:1 per Beaumont standard of care (blood /cardioplegic solution), contains the following in a 500 cc bag of D5W (dextrose 5% in water): 50meq/L potassium chloride, 37.5 meq/L sodium bicarbonate and 7.5 meq/L magnesium sulfate. 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 as needed. The cardioplegic solution was delivered at a temperature of 4°C - 8°C.

Drug: Cold Blood Cardioplegia

Interventions

Custodiol HTK DRUG

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.

Also known as: Histidine-tryptophan-ketoglutarate cardioplegia solution

Cardioplegia: Custodiol HTK Solution

Cold Blood Cardioplegia DRUG

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.

Cold Blood Cardioplegia

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients undergoing scheduled cardiac surgery requiring cardioplegic arrest with expected cross clamp time\>45 minutes
• Patients age 18 and older

You may not qualify if:

• 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.

Sponsors & Collaborators

• Marc Sakwa, MD: lead
• Essential Pharmaceuticals, LLC: collaborator

Study Sites (1)

William Beaumont Hospital

Royal Oak, Michigan, 48073, United States

Location

Related Publications (21)

• Braathen B, Jeppsson A, Schersten H, Hagen OM, Vengen O, Rexius H, Lepore V, Tonnessen 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.

  PMID: 20800244 BACKGROUND

• Careaga G, Salazar D, Tellez S, Sanchez O, Borrayo G, Arguero 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. doi: 10.1016/s0188-4409(01)00296-x.

  PMID: 11440787 BACKGROUND

• 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.

  PMID: 8698763 BACKGROUND

• 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. doi: 10.1016/j.athoracsur.2004.10.003.

  PMID: 16039259 BACKGROUND

• Beyersdorf F, Krause E, Sarai K, Sieber B, Deutschlander 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. doi: 10.1055/s-2007-1013985.

  PMID: 2106735 BACKGROUND

• 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. doi: 10.1532/HSF98.20041145.

  PMID: 15769709 BACKGROUND

• Braathen B, Tonnessen 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.

  PMID: 19660338 BACKGROUND

• 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. doi: 10.1016/s0022-5223(99)70182-0.

  PMID: 10469959 BACKGROUND

• Aarsaether E, Stenberg TA, Jakobsen O, 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.

  PMID: 19628529 BACKGROUND

• 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. doi: 10.1055/s-2007-1020064.

  PMID: 3145585 BACKGROUND

• 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. doi: 10.1016/j.transproceed.2005.08.020.

  PMID: 16213352 BACKGROUND

• 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.

  PMID: 19324152 BACKGROUND

• 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.

  PMID: 3088335 BACKGROUND

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

  BACKGROUND

• 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. doi: 10.1016/s0967-2109(00)00087-9.

  PMID: 11250190 BACKGROUND

• 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. doi: 10.1016/S0022-5223(95)70195-8.

  PMID: 7776676 BACKGROUND

• 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. doi: 10.1111/j.1540-8191.1998.tb01053.x.

  PMID: 9892485 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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

  BACKGROUND

• 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.

  PMID: 10024809 BACKGROUND

MeSH Terms

Conditions

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Heart Valve Diseases

Interventions

Bretschneider cardioplegic solution

Condition Hierarchy (Ancestors)

Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Limitations and Caveats

Adverse events (not serious adverse events) are listed only for events occurring with greater than 5% frequency in at least one of the groups.

Results Point of Contact

• Title: Marc P. Sakwa, M.D.
• Organization: William Beaumont Hospital

marc.sakwa@beaumont.org

248/898-0123

Study Officials

• Marc Sakwa, M.D.

  Beaumont Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 10, 2012
• First Posted: September 7, 2012
• Study Start: August 1, 2012
• Primary Completion: August 1, 2014
• Study Completion: April 1, 2016
• Last Updated: August 6, 2019
• Results First Posted: March 1, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)