European Heart Journal (2020) 41, 3702–3710 CONGRESS doi:10.1093/eurheartj/ehaa651 Interventional cardiology The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial Anthony Mathur 1*, Francisco Fernández-Avilés2, Jozef Bartunek3, Ann Belmans4, Filippo Crea 5,6, Sheik Dowlut1, Manuel Galin ~ anes7, Marie-Claire Good8, Juha Hartikainen 9, Christine Hauskeller10, Stefan Janssens11, Petr Kala12, Jens Kastrup 13, John Martin14, Philippe Menasché15, Ricardo Sanz-Ruiz2, Seppo Ylä-Herttuala16, and Andreas Zeiher 17; On behalf of the BAMI Group† 1 Centre for Cardiovascular Medicine & Devices, Queen Mary University of London, London EC1M 6BQ, UK; 2Hospital General Universitario Gregorio Mara~ nón, Instituto de nón, CIBERCV, Madrid, Spain; 3Cardiovascular Center, OLV Hospital Aalst, Aalst, Belgium 4KU, Leuven, Leuven, Belgium; Investigación Sanitaria del Hospital Gregorio Mara~ 5 Catholic University of the Sacred Heart, Rome, Italy; 6Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; 7Department of Cardiac Surgery, Reparative Therapy of the Heart, Vall d’Hebron Research Institute, University Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain; 8Queen Mary University of London, London, UK; 9Kuopio University Hospital, Kuopio, Finland; 10University of Exeter, Exeter, UK; 11University Hospitals (UZ) Leuven, Belgium; 12University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic; 13Rigshospitalet and University of Copenhagen, Denmark; 14University College London, London, UK; 15Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou and University of Paris, Paris, France; 16University of Eastern Finland, Finland; and 17Department of Medicine III, Goethe University of Frankfurt, Frankfurt, Germany Received 30 June 2020; revised 16 July 2020; editorial decision 26 July 2020; accepted 28 July 2020; online publish-ahead-of-print 30 August 2020 See page 3711 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa802) Aims Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients follow- ing acute myocardial infarction (AMI), though existing trial results are inconsistent. ................................................................................................................................................................................................... Methods Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of and results intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ven- tricular ejection fraction (LVEF, <_45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low re- cruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2–8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48–7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84–7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0–5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7–12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group. ................................................................................................................................................................................................... Conclusions Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low re- cruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results. * Corresponding author. Tel: 02037658740; Email: a.mathur@qmul.ac.uk † See Supplementary material online, Appendix S6. VC The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com The BAMI Trial 3703 Graphical Abstract 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 ................................................................................................................................................................................................... Keywords ST-elevation myocardial infarction • Cell- and tissue-based therapy • Bone marrow cells .. Introduction .. Study design .. The autologous bone marrow cell therapy in acute myocardial infarction Despite more than two decades of pre-clinical and clinical research .. .. trial (BAMI) was a multicentre, pan-European, investigator led, random-3 testing the role of autologous cell-based therapies in the treatment of ... ized, open-label trial co-ordinated by Queen Mary University of London. cardiovascular disease, very few Phase III clinical trials have been con- .. The trial was performed in accordance with the principles of the .. Declaration of Helsinki. Approvals were obtained from local ethics com- ducted. Although attempts were made to unify the experimental .. approaches used1,2 (i.e. the type of cell, method, and timing of deliv- .. mittees and the pan-European Voluntary Harmonisation Procedure. .. Funding was provided by the European Union FP7 programme following ery), a multitude of Phase II trials have been published using differing .. methodologies. The European Society of Cardiology’s Task Force for .. a competitive application process. After a change in the regulatory proc- .. esses, all sites contributed additional funding to cover the resultant short- cell-based therapies in cardiovascular disease created a Consortium .. falls. The trial was designed and conducted by the BAMI Consortium and .. (listed in Supplementary material online, Appendix S1) to consolidate .. was co-ordinated from the BAMI Trial Office in London. this considerable pre-clinical research and design a definitive Phase III .. .. clinical trial. The Consortium gained funding from the European .. Study population Commission to design and deliver BAMI: A Phase III clinical trial of au- .. Patients 18 years of age or older with an acute ST-elevation myocardial .. tologous cell-based therapies in the treatment of acute myocardial in- .. infarction (as defined by the universal definition of AMI) undergoing acute farction (AMI). .. revascularization (i.e. either acute percutaneous coronary intervention .. .. (PCI) within 24 h of symptom onset or thrombolysis within 12 h, followed .. by acute PCI within 24 h after thrombolysis) were screened at investiga- .. Methods .. tional sites. .. The full final protocol can be found in Supplementary material online, .. PCI.Potentially The final eligible patients were consented following their primary eligibility criterion of <_45% left ventricular ejection fraction .. Appendix S2. . (LVEF), based on previous studies suggesting a beneficial effect of 3704 A. Mathur et al. Figure 1 CONSORT diagram for patient flow in the BAMI trial. .. excluded. The full list of the inclusion and exclusion criteria can be found cell therapies in patients with impaired cardiac function,4 was confirmed .. 2–6 days after the primary PCI by the central echocardiography core lab. .. in Supplementary material online, Appendix S2. .. Patients with cardiogenic shock on admission, and those that developed .. signs of heart failure following the primary PCI procedure, were .. .. The BAMI Trial 3705 .. treated group. All patients recruited would complete a 2-year follow-up, Bone marrow cell infusion .. Eligible patients were randomized to the control arm or treatment arm in .. even if the trial was stopped prematurely. Using an alpha-spending func- .. tion according to Lan-DeMets,11 450 events would have been required a 1:1 ratio, which was stratified by country (summarized in Figure 1). .. Patients in both arms underwent full medical optimization in alignment .. to have 90% statistical power to detect treatment effect, requiring the re- .. cruitment of 1500 patients to each arm. However, the aforementioned with existing local protocols. .. markedly reduced recruitment and lower than expected event rates For patients randomized to the treatment arm, a bone marrow aspir- .. ate was performed under local anaesthesia within 2–8 days of the primary .. meant that the trial’s statistical analysis would only be sufficient to report .. effect size based on the reduced number of patients. PCI. Fifty millilitres of bone marrow was drawn into 5 10 ml heparinized .. syringes. The aspirates were immediately transported to a dedicated cell .. Kaplan–Meier curves have summarized the overall mortality by treat- .. ment group and have not censored patients at 2 years, but have included processing facility where the bone marrow-derived mononuclear cells .. (BM-MNCs) were isolated using a Ficoll density gradient as per the .. their entire follow-up (i.e. up to their time of death, study completion or t2cure method (Supplementary material online, Appendix S3). Following .. study termination). Event rates at 2 years are presented together with .. their associated 95% confidence interval, obtained using a log(-log)- separation, the BM-MNCs were re-suspended in X-Vivo 10 medium and .. R returned to the source site in a CryocyteV bag. The BM-MNCs (range .. transformation. The treatment effect is estimated by means of a hazard .. ratio and its associated 95% confidence interval. 25–500  106 as per protocol) were infused into the culprit coronary ar- .. tery, that was treated with primary PCI at the index admission, using an .. Cumulative incidence functions (CIFs) and their 95% CIs at 2 years over-the-wire balloon that matched the vessel dimensions. Infusion used .. were calculated for the secondary endpoints and presented for each .. randomized arm. The treatment effect is estimated by means of a hazard the stop-flow technique: 3 min of balloon inflation with cells delivered .. through the central lumen of the catheter, followed by 3 min of flow with .. ratio for the sub-distribution hazard of the event of interest using a Fine– .. Gray regression model. The primary and secondary endpoints are ana- the balloon down.5 This cycle was repeated three times to deliver the full .. 10 mls of cells—3 stop-flow cycles of 3.3 ml each. Patients randomized to .. lysed for Full Analysis Set (FAS i.e. intention to treat) and Per Protocol the treatment arm were infused with BM-MNCs 2–8 days following the .. Set (PPS). .. primary PCI. Procedural anticoagulation was performed with bivalirudin .. The safety endpoints were analysed using the methods described for not heparin due to the possible interaction between the latter and the .. the secondary efficacy endpoints. For the analysis of adverse events, CIFs .. have been calculated up to 6 months as only serious events were BM-MNCs.6 .. .. reported thereafter. Additional analyses were performed for the occur- .. rence of any serious events within the Safety Set. For clarity, only the FAS Study outcomes .. The initial study plan was to demonstrate a 25% reduction in all-cause .. and Safety Set analyses are presented in the Results section. .. The FAS included all patients who were randomized according to their mortality at 2 years in patients treated with BM-MNCs. When the study .. randomized allocation. The Safety Set included all patients according to was conceived in 2011, contemporary data suggested an event (death) .. rate of 12% in patients with reduced LVEF7,8,9 and a sample size of 3000 .. their actual treatment, i.e. untreated patients randomized to BM-MNC .. were included in the control group. patients was calculated.3 The primary endpoint of the BAMI trial was the .. time from randomization to all-cause mortality. The secondary endpoints .. All significance testing was two-sided and done at a significance level of .. 5%. However, due to the nature of the trial, with the aim of the trial being included time from randomization to cardiac mortality, the composite of .. the estimation of event rates and treatment effects, all significance testing cardiovascular death or heart failure re-hospitalization, and the compos- .. ite of re-hospitalization for repeat myocardial infarction, revasculariza- .. is of a purely exploratory nature. No adjustment was made to the signifi- .. cance levels to account for multiple testing. tion, heart failure, implantable cardioverter-defibrillator (ICD), or stroke. .. Safety endpoints included: adverse events (collected up to 6 months) and .. All analyses were performed using SAS version 9.4 and SAS/STAT ver- .. sion 15.1 for Windows. serious adverse events, syncope, arrhythmia, neoplastic disease, and .. bleeds at 2 years. .. However, due to a combination of factors including a markedly .. .. reduced number of patients with LVEF <_45%, a reduction in the mortality .. Results in patients presenting with AMI (even with impaired left ventricular func- .. .. Patient and procedural characteristics tion), and a limitation on the duration of funding, the steering committee .. re-issued the statistical analysis plan to present the data as observational .. From the trial’s start date (10 September 2013) to the last recruited results (an ‘estimation’ trial10). This decision was scrutinized and .. .. patient (25 October 2017), 518 patients with local LV function approved by the sponsor and regulatory authorities with a view that the .. thought to be <_45% were screened, from which 375 patients were BAMI analysis would produce valuable indicators of effect size for future .. .. enrolled into the BAMI trial after core lab analysis confirmed an echo- studies. .. cardiographic LVEF <_45%. One hundred eighty-five patients were All study patients returned for an onsite visit 30 days after hospital dis- .. .. randomized to the BM-MNC group and 190 patients to the control charge. Patients then underwent follow-up by telephone every 3 months .. arm. Thirty-seven sites were initiated in the study, out of which 28 from randomization until the end of the trial hospital visit—each patient .. was followed up for a minimum of 2 years. Endpoints were reported .. contributed to recruitment and 23 delivered BM-MNC therapy (see .. Supplementary material online, Appendix S4 for the list of sites). In the throughout the follow-up period and were adjudicated by an independ- .. ent Clinical Event Committee (CEC, Supplementary material online, .. BM-MNC group, 161 patients received cell therapy [median BM- .. MNC infused 140  106, interquartile range (IQR) 138–340  106] Appendix S6) blinded to the patient treatment allocation. .. .. with 140 receiving cell therapy per protocol (see Supplementary ma- .. terial online, Appendix S5 for the breakdown in discrepancy between Statistical analysis .. The original trial design was event-driven using existing registry data that .. randomized and treated patients). suggested a 12% mortality at 2 years in the control group,3 which would .. The baseline characteristics of all trial participants are presented in .. be reduced to 9% (25% relative reduction, 1.355 hazard ratio) in the cell- . Table 1. Both groups were well matched for age, ethnicity, and vital 3706 A. Mathur et al. Table 1 Baseline characteristics for patients enrolled into BAMI Baseline characteristic Statistic BM-MNC Control Total P-value .................................................................................................................................................................................................................... Total population N 185 190 375 Age [years] [n] Mean (SD) [185] 59 (11) [190] 60 (11) [375] 59 (11) 0.29 Female (%) n/N (%) 30/185 (16.22) 43/190 (22.63) 73/375 (19.47) 0.12 Race White n/N (%) 165/185 (89.19) 179/190 (94.21) 344/375 (91.73) 0.15 Black n/N (%) 3/185 (1.62) 4/190 (2.11) 7/375 (1.87) Asian n/N (%) 12/185 (6.49) 6/190 (3.16) 18/375 (4.80) Other n/N (%) 5/185 (2.70) 1/190 (0.53) 6/375 (1.60) Vital signs Systolic BP [mmHg] [n] Mean (SD) [184] 114 (15) [190] 113 (18) [374] 114 (17) 0.63 Diastolic BP [mmHg] [n] Mean (SD) [183] 69 (10) [190] 69 (12) [373] 69 (11) 0.79 Heart rate [b.p.m.] [n] Mean (SD) [184] 77 (13) [190] 78 (12) [374] 77 (13) 0.58 Killip class 1 n/N (%) 140/176 (79.55) 136/179 (75.98) 276/355 (77.75) 0.28 2 n/N (%) 32/176 (18.18) 38/179 (21.23) 70/355 (19.72) 3 n/N (%) 2/176 (1.14) 5/179 (2.79) 7/355 (1.97) 4 n/N (%) 2/176 (1.14) 0/179 (0.00) 2/355 (0.56) Hypertension n/N (%) 83/185 (44.86) 94/190 (49.47) 177/375 (47.20) 0.41 Hypercholesterolaemia n/N (%) 69/185 (37.30) 72/190 (37.89) 141/375 (37.60) 0.92 Insulin-dependent diabetes n/N (%) 15/185 (8.11) 5/190 (2.63) 20/375 (5.33) 0.02 Non-insulin-dependent diabetes n/N (%) 23/185 (12.43) 17/190 (8.95) 40/375 (10.67) 0.32 Current smoker n/N (%) 79/185 (42.70) 76/190 (40.00) 155/375 (41.33) 0.60 Prior smoker n/N (%) 33/185 (17.84) 41/190 (21.58) 74/375 (19.73) 0.39 Prior MI n/N (%) 21/185 (11.35) 10/189 (5.29) 31/374 (8.29) 0.04 Prior percutaneous revascularization n/N (%) 19/185 (10.27) 6/189 (3.17) 25/374 (6.68) 0.01 CABG n/N (%) 0/185 (0.00) 2/189 (1.06) 2/374 (0.53) 0.50 Stroke n/N (%) 5/185 (2.70) 3/189 (1.59) 8/374 (2.14) 0.50 Renal insufficiency n/N (%) 8/185 (4.32) 5/189 (2.65) 13/374 (3.48) 0.41 Malignancy n/N (%) 5/185 (2.70) 13/189 (6.88) 18/374 (4.81) 0.09 Time intervals Time from onset to PCI [h] [n] Median (Q1; Q3) [176] 3.6 (2.2; 7.2) [187] 3.8 (2.3; 7.6) [363] 3.7 (2.3; 7.5) 0.64 Time from onset to randomization [h] [n] Median (Q1; Q3) [179] 81 (66; 106) [187] 80 (61; 103) [366] 81 (63; 103) 0.32 Time from PCI to randomization [h] [n] Median (Q1; Q3) [181] 74 (61; 97) [190] 73 (57; 97) [371] 74 (57; 97) 0.28 Location of culprit lesion LM n/N (%) 2/185 (1.08) 4/190 (2.11) 6/375 (1.60) 0.69 LAD n/N (%) 160/185 (86.49) 162/190 (85.26) 322/375 (85.87) 0.77 CX n/N (%) 6/185 (3.24) 9/190 (4.74) 15/375 (4.00) 0.60 RCA n/N (%) 17/185 (9.19) 15/190 (7.89) 32/375 (8.53) 0.71 Unknown n/N (%) 0/185 (0.00) 0/190 (0.00) 0/375 (0.00) Core Lab LVEF [%] [n] Mean (SD) [185] 39 (5) [190] 39 (5) [375] 39 (5) 0.24 .. signs. Nominal differences in pre-morbid state were observed; the .. In both groups, the culprit lesion was most frequently located in treatment arm contained more patients with insulin-dependent dia- .. the left anterior descending coronary artery (86.5% in the BM-MNC .. betes (8.1% in the BM-MNC arm and 2.6% in the control arm), prior .. and 85.3% control group). history of myocardial infarction (11.4% and 5.3%), and previous per- .. Echocardiographic ejection fraction as determined by the core lab .. cutaneous revascularization (10.3% and 3.2%). .. assessment prior to inclusion was 39% ± 5% in the BM-MNC and Primary PCI was performed in a timely manner from the onset of .. 39% ± 5% in the control group. .. chest pain in both groups [3.6 h (IQR 2.2–7.2) BM-MNC and 3.8 h .. (IQR 2.3–7.6) control]. Likewise, the time from PCI to randomization .. Endpoint analyses .. into the trial was similar for both groups [74 h (IQR 61–97) BM- .. The results are summarized in Table 2. There were six deaths in the MNC and 73 h (IQR 57–97) control]. .. BM-MNC group [n = 185, estimated event rate 3.26%, 95% The BAMI Trial 3707 Table 2 Summary of results of BAMI for the full analysis and safety sets Endpoints (Type of analyses BM-MNC N (esti- Control N (esti- Estimated hazard Event collection performed) mated events mated events ratio vs. control time rate%: 95% confi- rate%: 95% confi- (95% confidence dence interval) dence interval) interval) .................................................................................................................................................................................................................... Primary endpoint (Survival analyses performed) Full analysis set (N) 185 190 All-cause mortality 6 (3.3%:1.5 -7.1%) 7 (3.8%:1.8–7.8%) 0.85 (0.29–2.53) 2 years Secondary efficacy endpoints (Competing risk analyses performed) Cardiac mortality 3 (1.6%: 4 (2.2%: 0.75 2 years 0.5–4.4%) 0.7–5.2%) (0.17–3.32) Cardiovascular death or Re-hospitaliza- 9 (4.9%: 18 (9.7%: 0.48 2 years tion due to heart failure 2.4–8.7%) 6.0–14.5%) (0.22–1.06) Re-hospitalization due to re-myocardial 31 (16.9%: 40 (21.5%: 0.72 2 years infarction, revascularization, heart 11.9–22.7%) 15.9–27.7%) (0.45–1.14) failure, implantable cardioverter- defibrillator (ICD) or stroke Breakdown: • Re-hospitalization due to re-myocar- 5 (2.7%: 7 (3.8%: 0.701 2 years dial infarction 1.0–5.9%) 1.7–7.3%) (0.22–2.19) • Re-hospitalization due to 13 (7.1%: 14 (7.5%: 0.902 2 years revascularization 4.0–11.4%) 4.3–11.9%) (0.43–1.91) • Re-hospitalization due to heart failure 5 (2.7%: 15 (8.1%: 0.332 2 years 1.0–5.9%) 4.7–12.5%) (0.12–0.88) • Re-hospitalization due to ICD implant 10 (5.4%: 16 (8.7%: 0.614 2 years 2.8–9.4%) 5.2–13.4%) (0.28–1.35) • Re-hospitalization due to stroke 4 (2.2%: 0 (0.0%) Not calculable 2 years 0.7–5.1%) Secondary safety endpoints (Competing risk analyses performed) Safety set (N) 161 214 Any adverse events 101 (62.8%: 116 (54.9%: 1.20 6 months 54.8–69.8%) 47.9–61.4%) (0.92–1.55) Any serious adverse events 57 (41.5%: 78 (60.9%: 0.96 5 years 31.8–50.9%) 40.7–76.1%) (0.68–1.36) Re-hospitalization due to stroke* 7 (6.5%: 1 (1.1%: 9.17 5 years 2.4–13.4%) 0.1–5.5%) (1.14–73.47) Bleeds 28 (18.1%: 29 (14.2%: 1.29 5 years 12.4–24.6%) 9.8 -19.4%) (0.77- 2.16) Neoplastic disease 7 (6.6%: 8 (5.4%: 1.14 5 years 2.7–13.0%) 2.3–10.3%) (0.41 -3.12) Syncope 8 (6.5%: 7 (4.5%: 1.48 5 years 2.8–12.3%) 1.7–9.6%) (0.54–4.06) Arrhythmias (atrial fibrillation and ven- 9 (6.3%: 19 (9.6%: 0.60 5 years tricular tachycardia) 3.0–11.2%) 6.0–14.4%) (0.27–1.31) *Rehospitalization due to stroke is an efficacy endpoint, but additional safety analysis has been performed. .. confidence interval (CI): 1.48–7.12%] and seven deaths in the control .. CI: 0.45–4.37%) and four cardiac deaths in the control group (2.18%, group (n = 190, 3.82%, 95% CI: 1.84–7.84% control) (Figure 2A). .. 95% CI: 0.72–5.15%). Kaplan–Meier curves illustrate the temporal oc- .. There were three cardiac deaths in the BM-MNC group (1.63%, 95% . currence of the composite secondary endpoints in Figure 2C and D. 3708 A. Mathur et al. Figure 2 Kaplan–Meier curves showing primary and secondary endpoint results in the BAMI trial: (A) Primary endpoint—all-cause mortality up to 2 years (full analysis set). (B) Secondary endpoint—cumulative incidence functions for cardiac death up to 2 years (full analysis set). (C) Secondary endpoint—cumulative incidence functions for cardiovascular death or re-hospitalization due to heart failure up to 2 years (full analysis set). (D) Secondary endpoint—cumulative incidence functions for re-hospitalization due to repeat myocardial infarction, revascularization, heart failure, implantable cardioverter-defibrillator, or stroke up to 2 years (full analysis set). Analysis of the secondary endpoints (FAS) demonstrated that five .. trial in patients with successfully re-perfused AMI and depressed LV .. patients in the BM-MNC group were re-hospitalized due to heart fail- .. function 2–6 days post-reperfusion therapy. Consequently, no group .. ure (2.7%, 95% CI: 1.0–5.9%) and 15 patients (8.1%, CI: 4.7–12.5%) in .. comparisons are possible and the data presented are descriptive in the control group (Table 2). Four patients in the BM-MNC group .. nature. However, since BAMI is the largest trial investigating the use .. (2.2%, 95% CI: 0.7–5.1%) and 0 patients in the control group were .. of autologous BM-MNC administration in AMI, we believe that the hospitalized due to stroke (Table 2). Site-based assessment of each .. results do provide insights into the future of new therapeutics in the .. individual stroke hospitalization (which occurred 1–19 months .. treatment of AMI, and the challenges of designing and conducting tri- .. als of autologous BM-MNC-based therapies in AMI. post-cell infusion) did not suggest that these events were related to .. BM-MNC therapy. .. Firstly, one of the most striking observations is the trial’s very low .. mortality rate. When the study was conceived in 2011 existing regis- Figure 3 illustrates cumulative event rates in both groups for any .. adverse event (Figure 3A), any serious adverse event (Figure 3B), re- .. tries suggested that in patients with an LVEF <_45% post-reperfusion .. therapy, an all-cause mortality of 12% at 2 years could be hospitalization for stroke (Figure 3C), and the occurrence of bleeding .. (Figure 3D). .. expected3,7,9 reflecting the result of primary angioplasty services that .. .. were in evolution during the preceding years. Moreover, the .. REPAIR-AMI trial, performed in 2004 and 2005, showed that the .. Discussion .. beneficial effects of BM-MNC administration on clinical outcome .. (mortality and re-hospitalization for heart failure) was entirely .. Given the low recruitment and event rates, BAMI does not qualify for .. confined to patients with a baseline LVEF <_45%. Finally, in BAMI, assessing the efficacy of the administration of autologous BM-MNCs .. all-cause mortality was chosen as the primary endpoint in order to .. on all-cause mortality, nor can it be viewed as a hypothesis-testing . mitigate any effects of the open-label trial design without a placebo The BAMI Trial 3709 Figure 3 Kaplan–Meier curves showing safety and efficacy endpoints in the BAMI trial. (A) Cumulative incidence functions for any adverse event up to 6 months (safety set). (B) Cumulative incidence functions for serious adverse events up to 5 years (trial end) (safety set). (C) Cumulative inci- dence functions for re-hospitalization due to stroke up to 5 years (trial end) (safety set). (D) Cumulative incidence functions for bleeding up to 5 years (trial end) (safety set). control group, as the intracoronary instrumentation for infusion of a .. hospitalization for heart failure occurs very infrequently during .. placebo preparation was previously criticized as it may increase event .. 2 years of follow-up, even in patients with a mean LVEF of 39% within rates in the placebo group and, thereby, skew the results towards the .. 2–6 days of successful acute PCI for AMI. .. treatment arm. The trial’s very low all-cause mortality (composite of .. Thus, for future trials, the logistical and regulatory considerations 3.5%) demonstrates the overwhelmingly successful implementation .. currently required to administer cell-based products,12 even if effi- .. of primary angioplasty across the 28 recruiting sites in 10 European .. cacy is shown, could only be offset by seeing a dramatic beneficial ef- .. countries, as well as the effectiveness of concomitant medical ther- .. fect of BM-MNC therapy. Given the low event rate seen in BAMI, the apy. Likewise, the difficulty in identifying patients with an ejection frac- .. number of patients needed to demonstrate a significant treatment ef- .. tion <_45% also points to the success in improved management of .. fect, and the logistical costs involved, it is suggested that future trials myocardial infarction in BAMI sites. Thus, if all-cause mortality is the .. would be prohibitively expensive. It is important to consider that the .. primary outcome of a trial of new therapeutics for myocardial infarc- .. largest advance in the treatment of AMI in recent years has been pri- tion, the sample size of enrolled patients will need to be much larger .. mary angioplasty, which was affected by a change in clinical pathways, .. (over 10 000 patients, using a mortality rate of 3.5%). This would like- .. not the discovery of a new therapeutic. Whether BM-MNC therapy ly make the trial futile based on cost and logistics. This suggests that .. has a role in other forms of cardiac disease (e.g. heart failure and re- .. future studies will need careful consideration with respect to target .. fractory angina13,14) remains to be seen. population and the use of composite endpoints to meet regulatory .. The BAMI trial was pivotal due to several important considera- .. approval. .. tions. This was the first attempt at a Phase III study of BM-MNC ther- Notwithstanding all these limitations, the results of the present .. apy in the treatment of AMI delivered by an academic Consortium. .. study illustrate that besides the very low mortality rates, re- . The Consortium achieved an agreement on a definitive trial design 3710 A. Mathur et al. .. 2. Mathur A, Fernández-Avilés F, Dimmeler S, Hauskeller C, Janssens S, Menasche based on existing Phase II trial data collected over the preceding dec- .. ade (which included patient selection, the processing of cells and the .. P, Wojakowski W, Martin J, Zeiher A, the BAMI Investigators. The consensus of .. the Task Force of the European Society of Cardiology concerning the clinical in- timing of infusion) and took into consideration the various changes in .. vestigation of the use of autologous adult stem cells for the treatment of acute regulatory approvals that occurred between the trial’s planning and .. myocardial infarction and heart failure: update 2016. Eur Heart J 2017;38: .. 2930–2935. completion. The BAMI trial most closely followed the design and .. 3. Mathur A, Arnold R, Assmus B, Bartunek J, Belmans A, Bönig H, Crea F, methodologies used in the Phase II REPAIR-AMI study, including the .. .. Dimmeler S, Dowlut S, Fernández-Avilés F, Gali~ nanes M, Garcia-Dorado D, delivery of the same order of magnitude of cells. REPAIR-AMI dem- .. Hartikainen J, Hill J, Hogardt-Noll A, Homsy C, Janssens S, Kala P, Kastrup J, .. Martin J, Menasche P, Miklik R, Mozid A, Román J, Sanz-Ruiz R, Tendera M, onstrated improved clinical outcomes including mortality and re- .. Wojakowski W, Ylä-Herttuala S, Zeiher A. The effect of intracoronary infusion hospitalization for heart failure in patients with reduced LVEF during .. of bone marrow-derived mononuclear cells on all-cause mortality in acute myo- .. cardial infarction: rationale and design of the BAMI trial. Eur J Heart Fail 2017;19: long-term follow-up after AMI, but was performed in 2004 and .. 2005.15 Furthermore, meta-analyses demonstrated a signal towards .. 1545–1550. .. 4. Assmus B, Leistner DM, Schächinger V, Erbs S, Elsässer A, Haberbosch W, reduced mortality and morbidity following BM-MNC therapy16,17; .. Hambrecht R, Sedding D, Yu J, Corti R, Mathey DG, Barth C, Mayer-Wehrstein this was in the context of clinical trials of cell-based therapies in .. C, Burck I, Sueselbeck T, Dill T, Hamm CW, Tonn T, Dimmeler S, Zeiher AM, .. Estel S, Braun H, Geweyer I, Palapies L, REPAIR-AMI Study Group. Long-term patients with AMI which initially did not show dramatic changes in .. clinical outcome after intracoronary application of bone marrow-derived mono- .. LVEF, but went on to show significant reductions in mortality.18 .. nuclear cells for acute myocardial infarction: migratory capacity of administered The trial’s conduct highlighted several important difficulties regard- .. cells determines event-free survival. Eur Heart J 2014;35:1275–1283. .. 5. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann ing the regulatory processes surrounding the use of cell-based prod- .. H, Yu J, Corti R, Mathey D, Hamm C, Süselbeck T, Assmus B, Tonn T, Dimmeler ucts in large multicentre, pan-European studies. Although ultimately .. S, Zeiher A; REPAIR-AMI Investigators. Intracoronary bone marrow-derived pro- .. genitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210–1221. the logistical issues were solved, the cost in time and money signifi- .. 6. Seeger FH, Rasper T, Fischer A, Muhly-Reinholz M, Hergenreider E, Leistner D, cantly impacted the success of the trial.19 .. .. Sommer K, Manavski Y, Henschler R, Chavakis E, Assmus B, Zeiher A, Dimmeler In conclusion, while BAMI cannot provide any definitive answers .. 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 regarding the effect of BM-MNC therapy on all-cause mortality in .. 2012;111:854–862. AMI patients due to the significant under recruitment, it did demon- .. 7. Ng VG, Lansky AJ, Meller S, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie B, .. Shah R, Mehran R, Stone GW. The prognostic importance of left ventricular strate that autologous cell-based therapy can be delivered following .. AMI in multiple sites across Europe. The very low 2-year all-cause .. function in patients with ST-segment elevation myocardial infarction: the .. HORIZONS-AMI trial. Eur Heart J Acute Cardiovasc Care 2014;3:67–77. mortality rate, and the small number of patients developing post- .. 8. Sutton NR, Li S, Thomas L, Wang T, Lemos J, Enriquez J, Shah R, Fonarow G. infarction heart failure within 2 years following primary angioplasty .. The association of left ventricular ejection fraction with clinical outcomes after .. myocardial infarction: findings from the Acute Coronary Treatment and for AMI provides useful information regarding the challenges and diffi- .. Intervention Outcomes Network (ACTION) Registry-Get with the Guidelines .. (GWTG) Medicare-linked database. Am Heart J 2016;178:65–73. culties involved in future trials of cell-based therapies. .. .. 9. Daneault B, Généreux P, Kirtane AJ, Witzenbichler B, Guagliumi G, Paradis JM, .. Fahy MP, Mehran R, Stone GW. Comparison of Three-year outcomes after pri- .. mary percutaneous coronary intervention in patients with left ventricular ejec- Supplementary material .. .. tion fraction <40% versus >_ 40% (from the HORIZONS-AMI trial). Am J Cardiol 2013;111:12–20. .. 10. Claridge-Chang A, Assam PN. Estimation statistics should replace significance Supplementary material is available at European Heart Journal online. .. .. testing. Nat Methods 2016;13:108–109. Acknowledgements .. 11. Lan KKG, DeMets DL. Trust discrete sequential boundaries for clinical trials. .. Biometrika 1983;70:659–663. We would like to acknowledge the financial contribution to the trial .. 12. Hauskeller C, Baur N, Harrington J. Standards, harmonization and cultural differ- made by the Williamson Trust. .. ences: examining the implementation of a European Stem Cell Clinical Trial. Sci .. Culture 2019;28:174–199. .. 13. Hamshere S, Arnous S, Choudhury T, Choudry F, Mozid A, Yeo C, Barrett C, Funding .. .. Saunders N, Gulati A, Knight C, Locca D, Davies C, Cowie MR, Prasad S, Parmar This work was supported by the European Commission under the 7th .. M, Agrawal S, Jones D, Martin J, McKenna W, Mathur A. Randomized trial of Framework Programme (Grant Agreement number 278967). .. combination cytokine and adult autologous bone marrow progenitor cell admin- .. istration in patients with non-ischaemic dilated cardiomyopathy: the Conflict of interest: J.B. reports grants from European Union FP7 .. REGENERATE-DCM clinical trial. Eur Heart J 2015;36:3061–3069. .. 14. Henry TD, Losordo DW, Traverse JH, Schatz RA, Jolicoeur EM, Schaer GL, Grant received by Cardiovascular Research Centre Aalst, during the con- .. duct of the study; F.C. reports personal fees from Biotronic, Amgen, .. Clare R, Chiswell K, White CJ, Fortuin FD, Kereiakes DJ, Zeiher AM, Sherman .. W, Hunt AS, Povsic TJ. Autologous CD34þ cell therapy improves exercise cap- Astra Zeneca, Servier, Menarini, and BMS, outside the submitted work; .. acity, angina frequency and reduces mortality in no-option refractory angina: a J.H. reports grants from Ministry of Social Affairs and Health (Finland), .. patient-level pooled analysis of randomized double-blinded trials. Eur Heart J during the conduct of the study; A.Z. reports personal fees from Sanofi, .. 2018;39:2208–2216. .. 15. Assmus B, Rolf A, Erbs S, ElsäSser A, Haberbosch W, Hambrecht R, Tillmanns Boehringer Ingelheim, Amgen, and Novo Nordisk, outside the submitted .. H, Yu J, Corti R, Mathey DG, Hamm CW, SüSelbeck T, Tonn T, Dimmeler S, work; and Co-founder and scientific advisor of t2cure, manufacturer of .. .. Dill T, Zeiher AM, SchäChinger V, REPAIR-AMI Investigators. Clinical outcome 2 cellular products. All other authors reported no conflict of interest. .. years after intracoronary administration of bone marrow-derived progenitor .. cells in acute myocardial infarction. Circ Heart Fail 2010;3:89–96. .. 16. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. References .. Heart failure adult bone marrow cell therapy improves survival and induces 1. Bartunek J, Dimmeler S, Drexler H, Fernández-Avilés F, Galinanes M, Janssens S, .. long-term improvement in cardiac parameters a systematic review and meta- Martin J, Mathur A, Menasche P, Priori S, Strauer B, Tendera M, Wijns W, Zeiher .. .. analysis. Circulation 2012;126:551–568 A. The consensus of the task force of the European Society of Cardiology con- .. 17. Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, Watt SM. cerning the clinical investigation of the use of autologous adult stem cells for re- .. Autologous bone marrow stem cells to treat acute myocardial infarction: a sys- pair of the heart. 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