Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: The randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial

Circulation

Volumn 131, Issue 10, 2015, Pages 851-860

  Teraa, Martin ^a   Sprengers, Ralf W ^a   Schutgens, Roger E G ^b   Slaper Cortenbach, Ineke C M ^a   Van Der Graaf, Yolanda ^a   Algra, Ale ^a   Van Der Tweel, Ingeborg ^a   Doevendans, Pieter A ^a   Mali, Willem P Th M ^a   Moll, Frans L ^a   Verhaar, Marianne C ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

Atherosclerosis; Cells; Peripheral vascular diseases

Indexed keywords

PLACEBO;

ADULT; AGED; ANKLE BRACHIAL INDEX; ARTICLE; BONE MARROW DERIVED MONONUCLEAR CELL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; ENDOTHELIAL PROGENITOR CELL; FEMALE; FOLLOW UP; HOSPITALIZATION; HUMAN; INTRAARTERIAL DRUG ADMINISTRATION; LIMB ISCHEMIA; MAJOR CLINICAL STUDY; MALE; OUTCOME ASSESSMENT; OXYGEN TENSION; PRIORITY JOURNAL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL; RISK FACTOR; TISSUE PERFUSION; AMPUTATION; ANGIOGENESIS; BIOLOGICAL THERAPY; BONE MARROW TRANSPLANTATION; CLINICAL TRIAL; COMPLICATION; ISCHEMIA; KAPLAN MEIER METHOD; LIMB; MIDDLE AGED; MORTALITY; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PROCEDURES; STATISTICS AND NUMERICAL DATA; SURVIVAL RATE; TREATMENT OUTCOME; VASCULARIZATION;

AGED; AMPUTATION; BONE MARROW TRANSPLANTATION; CELL- AND TISSUE-BASED THERAPY; DOUBLE-BLIND METHOD; EXTREMITIES; FEMALE; FOLLOW-UP STUDIES; HUMANS; INFUSIONS, INTRA-ARTERIAL; ISCHEMIA; KAPLAN-MEIER ESTIMATE; MALE; MIDDLE AGED; NEOVASCULARIZATION, PHYSIOLOGIC; PERIPHERAL ARTERIAL DISEASE; QUALITY OF LIFE; RISK FACTORS; SURVIVAL RATE; TREATMENT OUTCOME;

EID: 84929516694     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.114.012913     Document Type: Article

References (48)

1. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366:1925-1934. doi: 10.1016/S0140-6736(05)67704-5.
2. Stoyioglou A, Jaff MR. Medical treatment of peripheral arterial disease: a comprehensive review. J Vasc Interv Radiol. 2004;15:1197-1207. doi: 10.1097/01.RVI.0000137978.15352.C6.
3. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45(suppl S):S5-67. doi: 10.1016/j.jvs.2006.12.037.
4. Becker F, Robert-Ebadi H, Ricco JB, Setacci C, Cao P, de Donato G, Eckstein HH, De Rango P, Diehm N, Schmidli J, Teraa M, Moll FL, Dick F, Davies AH, Lepäntalo M, Apelqvist J. Chapter I: Definitions, epidemiology, clinical presentation and prognosis. Eur J Vasc Endovasc Surg. 2011;42(suppl 2):S4-12. doi: 10.1016/S1078-5884(11)60009-9.
5. Conte MS, Geraghty PJ, Bradbury AW, Hevelone ND, Lipsitz SR, Moneta GL, Nehler MR, Powell RJ, Sidawy AN. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg. 2009;50:1462-1473.
6. Van Hattum ES, Tangelder MJ, Lawson JA, Moll FL, Algra A. Long-term risk of vascular events after peripheral bypass surgery. A cohort study. Thromb Haemost. 2012;108:543-553. doi: 10.1160/TH11-12-0844.
7. Sprengers RW, Teraa M, Moll FL, de Wit GA, van der Graaf Y, Verhaar MC. Quality of life in patients with no-option critical limb ischemia underlines the need for new effective treatment. J Vasc Surg. 2010;52:843-849.
8. Barshes NR, Chambers JD, Cohen J, Belkin M. Cost-effectiveness in the contemporary management of critical limb ischemia with tissue loss. J Vasc Surg. 2012;56:1015-1024.
9. Peters EJ, Childs MR, Wunderlich RP, Harkless LB, Armstrong DG, Lavery LA. Functional status of persons with diabetes-related lower-extremity amputations. Diabetes Care. 2001;24:1799-1804.
10. Hirsch AT, Hartman L, Town RJ, Virnig BA. National health care costs of peripheral arterial disease in the Medicare population. Vasc Med. 2008;13:209-215. doi: 10.1177/1358863X08089277.
11. Makdisse M, Pereira Ada C, Brasil Dde P, Borges JL, Machado-Coelho GL, Krieger JE, Nascimento Neto RM, Chagas AC; Hearts of Brazil Study and Peripheral Arterial Disease Committee of the Brazilian Society of Cardiology/Funcor. Prevalence and risk factors associated with peripheral arterial disease in the Hearts of Brazil Project. Arq Bras Cardiol. 2008;91:370-382.
12. Eraso LH, Fukaya E, Mohler ER 3rd, Xie D, Sha D, Berger JS. Peripheral arterial disease, prevalence and cumulative risk factor profile analysis. Eur J Prev Cardiol. 2012;21:704-711. doi: 10.1177/2047487312452968.
13. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T; Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. 2002;360:427-435. doi: 10.1016/S0140-6736(02)09670-8.
14. Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis. 2010;209:10-17. doi: 10.1016/j.atherosclerosis.2009.08.033.
15. Teraa M, Sprengers RW, van der Graaf Y, Peters CE, Moll FL, Verhaar MC. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg. 2013;258:922-929. doi: 10.1097/SLA.0b013e3182854cf1.
16. Sprengers RW, Moll FL, Teraa M, Verhaar MC; JUVENTAS Study Group. Rationale and design of the JUVENTAS trial for repeated intraarterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia. J Vasc Surg. 2010;51:1564-1568. doi: 10.1016/j.jvs.2010.02.020.
17. Sprengers RW, Lips DJ, Moll FL, Verhaar MC. Progenitor cell therapy in patients with critical limb ischemia without surgical options. Ann Surg. 2008;247:411-420. doi: 10.1097/SLA.0b013e318153fdcb.
18. Yoshida M, Horimoto H, Mieno S, Nomura Y, Okawa H, Nakahara K, Sasaki S. Intra-arterial bone marrow cell transplantation induces angiogenesis in rat hindlimb ischemia. Eur Surg Res. 2003;35:86-91. doi: 69401.
19. 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;167:989-997. doi: 10.1001/archinte.167.10.989.
20. Lipinski MJ, Biondi-Zoccai GG, Abbate A, Khianey R, Sheiban I, Bartunek J, Vanderheyden M, Kim HS, Kang HJ, Strauer BE, Vetrovec GW. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol. 2007;50:1761-1767. doi: 10.1016/j.jacc.2007.07.041.
21. Ware JE, Kosinski M. SF-36 Physical and Mental Health Summary Scales: A Manual for Users of Version 1. Lincoln, RI: QualityMetric Incorporated; 2001.
22. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997;35:1095-1108.
23. Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT, Stern TP, Watling S, Bartel RL. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther. 2012;20:1280-1286. doi: 10.1038/mt.2012.52.
24. Benoit E, O'Donnell TF Jr, Kitsios GD, Iafrati MD. Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement. J Vasc Surg. 2012;55:781-789. doi: 10.1016/j.jvs.2011.10.089.
25. Lepäntalo M, Mätzke S. Outcome of unreconstructed chronic critical leg ischaemia. Eur J Vasc Endovasc Surg. 1996;11:153-157.
26. Kawamura A, Horie T, Tsuda I, Ikeda A, Egawa H, Imamura E, Iida J, Sakata H, Tamaki T, Kukita K, Meguro J, Yonekawa M, Kasai M. Prevention of limb amputation in patients with limbs ulcers by autologous peripheral blood mononuclear cell implantation. Ther Apher Dial. 2005;9:59-63. doi: 10.1111/j.1774-9987.2005.00218.x.
27. Kawamura A, Horie T, Tsuda I, Abe Y, Yamada M, Egawa H, Iida J, Sakata H, Onodera K, Tamaki T, Furui H, Kukita K, Meguro J, Yonekawa M, Tanaka S. Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs. J Artif Organs. 2006;9:226-233. doi: 10.1007/s10047-006-0351-2.
28. Whitehead J. The Design and Analysis of Sequential Clinical Trials. Chichester, UK: John Wiley & Sons Ltd; 1997.
29. MPS Research Unit: PEST 4: Operating Manual. Reading, UK: University of Reading; 2000.
30. Schulz KF, Grimes DA. Multiplicity in randomised trials I: endpoints and treatments. Lancet. 2005;365:1591-1595. doi: 10.1016/S0140-6736(05)66461-66466.
31. Iafrati MD, Hallett JW, Geils G, Pearl G, Lumsden A, Peden E, Bandyk D, Vijayaraghava KS, Radhakrishnan R, Ascher E, Hingorani A, Roddy S. Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J Vasc Surg. 2011;54:1650-1658. doi: 10.1016/j.jvs.2011.06.118.
32. Losordo DW, Kibbe MR, Mendelsohn F, Marston W, Driver VR, Sharafuddin M, Teodorescu V, Wiechmann BN, Thompson C, Kraiss L, Carman T, Dohad S, Huang P, Junge CE, Story K, Weistroffer T, Thorne TM, Millay M, Runyon JP, Schainfeld R; Autologous CD34+ Cell Therapy for Critical Limb Ischemia Investigators. A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia. Circ Cardiovasc Interv. 2012;5:821-830. doi: 10.1161/CIRCINTERVENTIONS.112.968321.
33. Szabó GV, Kövesd Z, Cserepes J, Daróczy J, Belkin M, Acsády G. Peripheral blood-derived autologous stem cell therapy for the treatment of patients with late-stage peripheral artery disease-results of the short- and long-term follow-up. Cytotherapy. 2013;15:1245-1252. doi: 10.1016/j.jcyt.2013.05.017.
34. Gupta PK, Chullikana A, Parakh R, Desai S, Das A, Gottipamula S, Krishnamurthy S, Anthony N, Pherwani A, Majumdar AS. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med. 2013;11:143. doi: 10.1186/1479-5876-11-143.
35. Li M, Zhou H, Jin X, Wang M, Zhang S, Xu L. Autologous bone marrow mononuclear cells transplant in patients with critical leg ischemia: preliminary clinical results. Exp Clin Transplant. 2013;11:435-439. doi: 10.6002/ect.2012.0129.
36. Gu YQ, Zhang J, Guo LR, Qi LX, Zhang SW, Xu J, Li JX, Luo T, Ji BX, Li XF, Yu HX, Cui SJ, Wang ZG. Transplantation of autologous bone marrow mononuclear cells for patients with lower limb ischemia. Chin Med J (Engl). 2008;121:963-967.
37. Klepanec A, Mistrik M, Altaner C, Valachovicova M, Olejarova I, Slysko R, Balazs T, Urlandova T, Hladikova D, Liska B, Tomka J, Vulev I, Madaric J. No difference in intra-arterial and intramuscular delivery of autologous bone marrow cells in patients with advanced critical limb ischemia. Cell Transplant. 2012;21:1909-1918. doi: 10.3727/096368912X636948.
38. Onodera R, Teramukai S, Tanaka S, Kojima S, Horie T, Matoba S, Murohara T, Matsubara H, Fukushima M; BMMNC Follow-Up Study Investigators; M-PBMNC Follow-Up Study Investigators. Bone marrow mononuclear cells versus G-CSF-mobilized peripheral blood mononuclear cells for treatment of lower limb ASO: pooled analysis for long-term prognosis. Bone Marrow Transplant. 2011;46:278-284. doi: 10.1038/bmt.2010.110.
39. Walter DH, Krankenberg H, Balzer JO, Kalka C, Baumgartner I, Schlüter M, Tonn T, Seeger F, Dimmeler S, Lindhoff-Last E, Zeiher AM; PROVASA Investigators. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA). Circ Cardiovasc Interv. 2011;4:26-37. doi: 10.1161/CIRCINTERVENTIONS.110.958348.
40. Assmus B, Tonn T, Seeger FH, Yoon CH, Leistner D, Klotsche J, Schächinger V, Seifried E, Zeiher AM, Dimmeler S. Red blood cell contamination of the final cell product impairs the efficacy of autologous bone marrow mononuclear cell therapy. J Am Coll Cardiol. 2010;55:1385-1394. doi: 10.1016/j.jacc.2009.10.059.
41. Seeger FH, Rasper T, Fischer A, Muhly-Reinholz M, Hergenreider E, Leistner DM, Sommer K, Manavski Y, Henschler R, Chavakis E, Assmus B, Zeiher AM, Dimmeler S. Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrow-derived mononuclear cells used for cardiovascular repair. Circ Res. 2012;111:854-862. doi: 10.1161/CIRCRESAHA.112.265678.
42. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J. 2007;28:766-772. doi: 10.1093/eurheartj/ehl509.
43. Britten MB, Abolmaali ND, Assmus B, Lehmann R, Honold J, Schmitt J, Vogl TJ, Martin H, Schächinger V, Dimmeler S, Zeiher AM. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation. 2003;108:2212-2218. doi: 10.1161/01.CIR.0000095788.78169.AF.
44. Teraa M, Sprengers RW, Westerweel PE, Gremmels H, Goumans MJ, Teerlink T, Moll FL, Verhaar MC; JUVENTAS study group. Bone marrow alterations and lower endothelial progenitor cell numbers in critical limb ischemia patients. PLoS One. 2013;8:e55592. doi: 10.1371/journal.pone.0055592.
45. Benoit E, O'Donnell TF Jr, Iafrati MD, Asher E, Bandyk DF, Hallett JW, Lumsden AB, Pearl GJ, Roddy SP, Vijayaraghavan K, Patel AN. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design. J Transl Med. 2011;9:165. doi: 10.1186/1479-5876-9-165.
46. Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, Silva GV, Lai D, Thomas JD, Kronenberg MW, Martin AD, Anderson RD, Traverse JH, Penn MS, Anwaruddin S, Hatzopoulos AK, Gee AP, Taylor DA, Cogle CR, Smith D, Westbrook L, Chen J, Handberg E, Olson RE, Geither C, Bowman S, Francescon J, Baraniuk S, Piller LB, Simpson LM, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moyé LA, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012;307:1717-1726. doi: 10.1001/jama.2012.418.
47. Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DX, Ellis SG, Forder JR, Anderson RD, Hatzopoulos AK, Penn MS, Perin EC, Chambers J, Baran KW, Raveendran G, Lambert C, Lerman A, Simon DI, Vaughan DE, Lai D, Gee AP, Taylor DA, Cogle CR, Thomas JD, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Kappenman C, Westbrook L, Piller LB, Simpson LM, Baraniuk S, Loghin C, Aguilar D, Richman S, Zierold C, Spoon DB, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moyé LA, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012;308:2380-2389. doi: 10.1001/jama.2012.28726.
48. Jeong H, Yim HW, Cho Y, Park HJ, Jeong S, Kim HB, Hong W, Kim H. The effect of rigorous study design in the research of autologous bone marrow-derived mononuclear cell transfer in patients with acute myocardial infarction. Stem Cell Res Ther. 2013;4:82. doi: 10.1186/scrt233.