Prospective, Controlled and Randomized Clinical Trial on Cardiac Cell Regeneration With Laser and Autologous Bone Marrow Stem Cells, in Patients With Coronary Disease and Refractory Angina

Coronary disease is one of the most frequent pathology of the modern world and the leading cause of death in the investigators country. In Spain more than 50.000 coronary percutaneous intervention and more than 5.000 coronary artery bypass graft (CABG) procedures are performed every year. Despite this data about 12% of patients have diffuse coronary disease and are not candidates to conventional therapies. Also between 15-25% of patients undergoing coronary bypass grafting receive an incomplete revascularization due to the poor quality of the coronary vessels.

Transmyocardial revascularization (TMR) is a surgical procedure that uses a laser to create channels through the myocardial, so this laser stimulates local angiogenesis and provides blood in the ischemic area. Results of this procedure have shown clear benefits in terms of reduction of angina and increase of survival of patients, compared to medical treatment.

Cell therapy in heart disease is offering in recent years encouraging results despite the methodological difficulties that being able to use this technique sometimes involves. The basis lies in the potential ability of stem cells to differentiate into any type of adult cell. In the case of cardiac cell therapy, stem cells can differentiate into myocardial cells or vascular cells capable of developing angiogenesis. Further studies are needed to draw firm conclusions about the clinical impact that the use of stem cells has on cardiovascular disease.

Recently a system has been developed to create, at the same time and in a simple and effective way, the laser channels and the introduction of stem cells on the edges of these channels. This system called PHOENIX ™ consists of a laser probe capable of creating transmural channels in the myocardium.

Based on the what has just been explained, it is quite possible that the combination of both therapies can increase successful results regarding the reduction in angina these patients need. Initially, and after having some experience with this type of treatment, the results could be analyzed and compared with the results obtained through laser therapy, with the help of a controlled clinical trial, such as the one the investigators are proposing.

Study Overview

• Status: Unknown
• Conditions: Coronary Disease; Angina
• Intervention / Treatment: Procedure: Transmyocardial revascularization (TMR) with Holmium YAG laser; Procedure: Transmyocardial revascularization (TMR) with Holmium YAG laser plus the patient's own stem cells extracted from bone marrow.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Guillermo Reyes Copa, Physician Doctor; Phone Number: +34915202268; Email: guillermo_reyes_copa@yahoo.es

Study Locations

• Spain
  • Madrid, Spain, 28006
    • Recruiting
    • Hospital Universitario de La Princesa
    • Contact: Guillermo Reyes Copa, Physician Doctor; Phone Number: +34915202268; Email: guillermo_reyes_copa@yahoo.es
    • Principal Investigator: Guillermo Reyes Copa, Physician Doctor
    • Sub-Investigator: José Manuel Nuche
    • Sub-Investigator: Juan Bustamante
    • Sub-Investigator: Pablo Álvarez
    • Sub-Investigator: Juan Duarte
    • Sub-Investigator: Adrián Alegre
    • Sub-Investigator: Beatriz Aguado
    • Sub-Investigator: Carmen Cámara
    • Sub-Investigator: Francisco Sánchez Madrid
    • Sub-Investigator: Cecilia Muñoz
    • Sub-Investigator: Luis Domínguez Gadea
    • Sub-Investigator: Maria José Olivera
    • Sub-Investigator: Paloma Caballero
    • Sub-Investigator: Francisco Abad Santos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients over 18 years of age.
• Patients with at least one area of myocardial ischemia or chronic myocardial infarction of the left ventricle demonstrated by any imaging technique not amenable to conventional revascularization and angina refractory to medical treatment.
• Ejection fraction> 25% measured in the six months prior to the procedure.
• Participants must be mentally competent to give consent for inclusion in the clinical trial

Exclusion Criteria:

• Patients with unstable angina defined as the need for intravenous nitrates at the time of surgery.
• Recent myocardial infarction (within 15 days before the procedure).
• Patients with decompensated heart failure at the time of surgery.
• Severe or life threatening arrhythmia (ventricular tachycardia or fibrillation) in the week before the procedure.
• Patients requiring some type of concomitant valvular surgery.
• Patients with severe obstructive lung disease criteria who are considered as not capable of bearing general anesthesia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment Control; Transmyocardial revascularization (TMR) with Holmium YAG (yttrium aluminium garnet) laser, according to habitual clinical practice in the Department of Cardiovascular Surgery.	Procedure: Transmyocardial revascularization (TMR) with Holmium YAG laser; Transmyocardial revascularization (TMR) is a surgical procedure that uses a laser to create channels through the myocardial, so this laser stimulates local angiogenesis and provides blood in the ischemic area.
Experimental: Experimental Treatment; Transmyocardial revascularization (TMR) with Holmium YAG laser plus the patient's own stem cells extracted from bone marrow.	Procedure: Transmyocardial revascularization (TMR) with Holmium YAG laser plus the patient's own stem cells extracted from bone marrow.; The system called PHOENIXTM consists of a laser probe with Holmium:YAG energy capable of creating transmural channels in the myocardium. Surrounding this fibre 3 needles with side holes are arranged so that the implantation of stem cells is done on the edges of the channel and not on the channel itself. This device is capable of distributing stem cells in those channels created by the laser, carrying out both procedures simultaneously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
New York Heart Association (NYHA)classification for angina	The main variable under study is the percentage of patients achieving a decrease in two levels of the NYHA classification for angina.	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The demographic, intra and postoperative variables	The demographic variables and patients' cardiovascular history will be collected. All the intra and postoperative variables will be collected, as well as the data obtained by cytometry (amount of cells injected into each appropriate patient)	one year
Tests	Before surgery and 12 months after it a test of ischemia provocation through isotopes will be carried out in order to measure the percentage of ischemic area (SPECT or Single Photon Emission Computed Tomography) and maximum effort capacity before the occurrence of the angina. The ejection fraction, the end-systolic volume and the end-diastolic volume of the left ventricle will be examined through an echocardiogram and a pre- and postoperative cardiac magnetic resonance imaging study.	one year
Quality of Life	The EQ-5D questionnaire (standardised instrument for use as a measure of health outcome)will be completed for the subjective assessment of the quality of life that the patient perceives to have.	one year

Collaborators and Investigators

• Sponsor: Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
• Investigators: Principal Investigator: Guillermo Reyes Copa, Physician Doctor, Cardiovascular Surgey Service, Hospital Universitario de La Princesa

Publications and helpful links

General Publications

• Lopez-Palop R, Moreu J, Fernandez-Vazquez F, Hernandez Antolin R. [Spanish Cardiac Catheterization and Coronary Intervention Registry. 15th official report of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology (1990-2005)]. Rev Esp Cardiol. 2006 Nov;59(11):1146-64. Spanish.
• Mukherjee D, Bhatt DL, Roe MT, Patel V, Ellis SG. Direct myocardial revascularization and angiogenesis--how many patients might be eligible? Am J Cardiol. 1999 Sep 1;84(5):598-600, A8. doi: 10.1016/s0002-9149(99)00387-2.
• Weintraub WS, Jones EL, Craver JM, Guyton RA. Frequency of repeat coronary bypass or coronary angioplasty after coronary artery bypass surgery using saphenous venous grafts. Am J Cardiol. 1994 Jan 15;73(2):103-12. doi: 10.1016/0002-9149(94)90198-8.
• Bridges CR, Horvath KA, Nugent WC, Shahian DM, Haan CK, Shemin RJ, Allen KB, Edwards FH; Society of Thoracic Surgeons. The Society of Thoracic Surgeons practice guideline series: transmyocardial laser revascularization. Ann Thorac Surg. 2004 Apr;77(4):1494-502. doi: 10.1016/j.athoracsur.2004.01.007.
• Allen KB, Dowling RD, Angell WW, Gangahar DM, Fudge TL, Richenbacher W, Selinger SL, Petracek MR, Murphy D. Transmyocardial revascularization: 5-year follow-up of a prospective, randomized multicenter trial. Ann Thorac Surg. 2004 Apr;77(4):1228-34. doi: 10.1016/j.athoracsur.2004.01.008.
• Allen KB, Dowling RD, Schuch DR, Pfeffer TA, Marra S, Lefrak EA, Fudge TL, Mostovych M, Szentpetery S, Saha SP, Murphy D, Dennis H. Adjunctive transmyocardial revascularization: five-year follow-up of a prospective, randomized trial. Ann Thorac Surg. 2004 Aug;78(2):458-65; discussion 458-65. doi: 10.1016/j.athoracsur.2004.04.049.
• Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, Zuba-Surma EK, Al-Mallah M, Dawn B. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007 May 28;167(10):989-97. doi: 10.1001/archinte.167.10.989.
• Haider HKh. Bone marrow cells for cardiac regeneration and repair: current status and issues. Expert Rev Cardiovasc Ther. 2006 Jul;4(4):557-68. doi: 10.1586/14779072.4.4.557.
• Haider HKh, Ashraf M. Bone marrow stem cell transplantation for cardiac repair. Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2557-67. doi: 10.1152/ajpheart.01215.2004.
• Anversa P, Leri A, Kajstura J, Nadal-Ginard B. Myocyte growth and cardiac repair. J Mol Cell Cardiol. 2002 Feb;34(2):91-105. doi: 10.1006/jmcc.2001.1506.
• Klein HM, Ghodsizad A, Borowski A, Saleh A, Draganov J, Poll L, Stoldt V, Feifel N, Piecharczek C, Burchardt ER, Stockschlader M, Gams E. Autologous bone marrow-derived stem cell therapy in combination with TMLR. A novel therapeutic option for endstage coronary heart disease: report on 2 cases. Heart Surg Forum. 2004;7(5):E416-9. doi: 10.1532/HSF98.20041095.
• Patel AN, Spadaccio C, Kuzman M, Park E, Fischer DW, Stice SL, Mullangi C, Toma C. Improved cell survival in infarcted myocardium using a novel combination transmyocardial laser and cell delivery system. Cell Transplant. 2007;16(9):899-905. doi: 10.3727/096368907783338253.
• Reyes G, Allen KB, Aguado B, Duarte J. Bone marrow laser revascularisation for treating refractory angina due to diffuse coronary heart disease. Eur J Cardiothorac Surg. 2009 Jul;36(1):192-4. doi: 10.1016/j.ejcts.2009.03.022. Epub 2009 Apr 25.
• Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977 Mar;21(3):247-54. doi: 10.1002/cpt1977213247.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Anticipated): October 1, 2012
• Study Completion (Anticipated): October 1, 2012

Study Registration Dates

• First Submitted: October 3, 2010
• First Submitted That Met QC Criteria: October 4, 2010
• First Posted (Estimate): October 5, 2010

Study Record Updates

• Last Update Posted (Estimate): November 30, 2010
• Last Update Submitted That Met QC Criteria: November 27, 2010
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Keywords: Stem cells; Refractory angina; Transmyocardial revascularization; Diffuse coronary disease not amenable to percutaneous coronary intervention, and angina, despite proper medical treatment
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Chest Pain; Coronary Artery Disease; Coronary Disease; Angina Pectoris
• Other Study ID Numbers: TMR-SC-02