European Heart Journal Advance Access originally published online on August 2, 2007
European Heart Journal 2007 28(17):2173-2174; doi:10.1093/eurheartj/ehm258
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Improved clinical outcome after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial: reply
J. W. Goethe Universität Frankfurt
Med. Klinik III
Abt.Kardiologie
Theodor-Stern-Kai 7
D-60590 Frankfurt a.M.
Germany
J. W. Goethe Universität Frankfurt
Med. Klinik III
Abt.Kardiologie
Theodor-Stern-Kai 7
D-60590 Frankfurt a.M.
Germany
J. W. Goethe Universität Frankfurt
Med. Klinik III
Abt.Kardiologie
Theodor-Stern-Kai 7
D-60590 Frankfurt a.M.
Germany
Tel: +49 69 6301 5789 Fax: +49 69 6301 6374 E-mail address: zeither{at}em.uni-frankfurt.de
Recently, Osterziel1 raised a question about the appropriateness of the clinical endpoints used in the REPAIR-AMI trial.2 Primary endpoint of the trial was the change in left ventricular ejection fraction, assessed by LV angiography.3 As such, the REPAIR-AMI trial was designed as a proof-of-concept trial, and intracoronary infusion of bone marrow-derived progenitor cells (BMC) is associated with improved left ventricular contractile function. Therefore, we are rather puzzled about the disappointment expressed by Osterziel,1 given that the trial was obviously not powered to and did never claim to detect differences in single clinical endpoints. It is universally accepted in phase II trials, such as the REPAIR-AMI, to assess safety aspects using a combined clinical endpoint, which may also generate hypotheses to be tested in subsequent larger clinical outcome trials. It might have escaped the attention of Osterziel1 that we had already presented the detailed analysis of the location of the recurrent myocardial infarctions in the supplement of our original article.2 Nevertheless, even when recurrent myocardial infarctions are limited to the target vessel, the combined endpoint of cardiovascular death, target vessel-related recurrent myocardial infarction, or rehospitalization for heart failure remains significantly reduced in patients receiving BMC compared with placebo [n = 11 (11%) vs. n = 2 (2%), P = 0.011]. Thus, these results are indeed encouraging to test the hypothesis, that intracoronary infusion of BMC improves clinical outcome in patients after an acute myocardial infarction.
Egeland and Brinchmann list a few points addressing the importance of cell processing in comparing the controversial results of the REPAIR-AMI trial and the ASTAMI trial.4
Ad 1: As recently published, comparison of different isolation protocols revealed a vastly reduced recovery of mononuclear cells from identical volumes of bone marrow aspirates when using the ASTAMI protocol.5 In addition, the cells' functional capacity, as measured by migratory capacity, colony forming unit capacity as well as in vivo recovery of blood flow in a hindlimb ischemia model were profoundly impaired, when the ASTAMI cell isolation protocol was used.5 Most importantly, the in vivo neovascularization capacity of patient-derived cells was completely abrogated, when the ASTAMI cell isolation/storage protocol was used.5 Thus, cell processing protocols profoundly interfere with functional capacity of bone marrow-derived progenitor cells.
Ad 2: The effects of different storage conditions and medium on progenitor cell functional parameters have extensively been studied and published.5 Obviously, the functional properties of progenitor cells mediating improved cardiac function after intracoronary administration are most likely different from the cell properties required to repopulate and reconstitute the bone marrow. In fact, it is well established that single cell transplantation is sufficient to reconstitute the bone marrow. Moreover, different integrins are used for homing of BMC to the bone marrow compared with the heart.
Ad 3: Even with respect to cell viability, which does not reflect functional activity of the cells, there are major differences between the different cell processing protocols. Median viability of injected cells was 95% in ASTAMI compared with 99% in the REPAIR-AMI trial. Notably, careful reading of the original report of the ASTAMI trial reveals that two of the 47 bone marrow-derived cell preparations were contaminated by bacteria.
Ad 4: Assessing colony forming unit capacity of bone marrow-derived cells from healthy controls is insufficient. At least in our view, it is absolutely mandatory to assess the functional capacity of patient-derived cells in experimental models, and this has to be done prior to embarking on a clinical trial.
Ad 5: The statement by Egeland and Brinchmann is incorrect. Of all the four controlled, randomized trials assessing the effects of BMC administration in acute myocardial infarction, ASTAMI stands out as the single trial with by far the lowest number of mononuclear cells infused (68 x 106)6 compared with the Leuven trial (172 x 106),7 REPAIR-AMI (198 x 106)3 (all median) and the BOOST trial (mean of 246 x 107).8 Moreover, experimental studies clearly documented a dose–response relationship, at least with respect to CD34+ cells.9
Taken together, it is indeed most likely that the different outcomes of the ASTAMI vs. the REPAIR-AMI trial are explained by the differences in cell functionality.
We appreciate the comments of Marenzi and Bartorelli.10 The time between myocardial infarction and intracoronary infusion therapy was nearly identical in the BMC and placebo group (median of 4 days), thus any spontaneous improvement in left ventricular ejection fraction (LVEF) prior to intracoronary infusion therapy may have occurred to the same extent in both groups. As suggested by Marenzi and Bartorelli, we re-analysed a potential effect of time to reperfusion therapy and infarct location on treatment effect by BMC administration. Randomization to BMC remained significantly associated with improved recovery of LVEF after adjusting for time to first reperfusion therapy (P = 0.013) as well as infarct location (anterior vs. inferior) (P = 0.021). There was no interaction between BMC treatment effect and infarct location (P = 0.87) or time to reperfusion (P = 0.60). Likewise, the beneficial effect of BMC administration on the combined clinical end point death, recurrent myocardial infarction, or revascularization procedures remained statistically significant in favour of BMC therapy, when adjusting for time to reperfusion therapy (P = 0.018) or infarct location (P = 0.013). Neither infarct location (P = 0.37) nor time to reperfusion (categorized according to the median of 4.5 h) (P = 0.47) was predictive for cardiovascular event rate. Thus, neither infarct location nor time to reperfusion had an impact on the results of the REPAIR-AMI trial, that intracoronary BMC administration favourably affects recovery of LVEF as well as clinical outcome.
References
- Osterziel KJ. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J (2007) 28:638.
[Free Full Text] - Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Werner N, Haase J, Neuzner J, Germing A, Mark B, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute smyocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J (2006) 27:2775–2783.
[Abstract/Free Full Text] - Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med (2006) 355:1210–1221.
[Abstract/Free Full Text] - Egeland T, Brinchmann JE. Cell quality in the ASTAMI study. Eur Heart J (2007) doi:10.1093/eurheartj/ehm125.
- 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.
[Abstract/Free Full Text] - Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med (2006) 355:1199–1209.
[Abstract/Free Full Text] - Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Maertens J, Rademakers F, Dymarkowski S, Gheysens O, Van Cleemput J, Bormans G, Nuyts J, Belmans A, Mortelmans L, Boogaerts M, Van de WF. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet (2006) 367:113–121.[CrossRef][Web of Science][Medline]
- Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet (2004) 364:141–148.[CrossRef][Web of Science][Medline]
- Kawamoto A, Iwasaki H, Kusano K, Murayama T, Oyamada A, Silver M, Hulbert C, Gavin M, Hanley A, Ma H, Kearney M, Zak V, Asahara T, Losordo DW. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation (2006) 114:2163–2169.
[Abstract/Free Full Text] - Marenzi G, Bartorelli AL. Improved clinical outcome after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J (2007) doi:10.1093/eurheartj/ehm257.
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