s
Percutaneous coronary intervention in acute myocardial infarction: from
procedural considerations to long term outcomes
Delewi, R.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Delewi, R. (2015). Percutaneous coronary intervention in acute myocardial infarction: from
procedural considerations to long term outcomes. Boxpress.
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Chapter 11
long term outcome after mononuclear bone marrow
or peripheral blood cells infusion after myocardial
infarction
Ronak Delewi, Anja M. van der Laan, Lourens F. H. J. Robbers, Alexander Hirsch, Robin Nijveldt, Pieter A. van der Vleuten, Jan G. P. Tijssen, René A. Tio, Johannes Waltenberger, Jurrien M. ten Berg, Pieter A. Doevendans, Helmut R. Gehlmann, Albert C. van Rossum, Jan J. Piek, Felix Zijlstra on behalf of the HEBE investigators.
ABSTRACT
Objectives This study reports the long-term follow-up of the randomised controlled HEBE trial. The HEBE study is a multicentre trial that randomised 200 patients with large first acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention to either intracoronary infusion of bone marrow mononuclear cells (BMMCs) (n=69), peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (n=65).
Methods In addition to 3–5 days, and 4 months after AMI, all patients underwent cardiac MRI after 2 years. A follow-up for 5 years after AMI was performed to assess clinical adverse events, including death, myocardial re-infarction and hospitalisation for heart failure.
Results Of the 200 patients enrolled, 9 patients died and 12 patients were lost to follow-up at 5 years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5±16.9 mL/m2) compared with (11.2±19.8 mL/m2, p=0.03) in the control
group, with no difference between the PBMC group (9.2±20.9 mL/m2) and controls
(p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (−1.8±15.0 mL/m2) as compared with controls (3.0±16.3 mL/m2, p=0.07),
with again no difference between PBMC (3.3±18.8 mL/m2) and controls (p=0.66). The
combined endpoint of death and hospitalisation for heart failure was non-significantly less frequent in the BMMC group compared with the control group (n=4 vs n=1, p=0.20), with no difference between PBMC and controls (n=6 vs n=4, p=0.74). The composite endpoint of death or recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008), with no difference between the BMMC group and controls (2 vs 3 patients, p=0.67).
Conclusions Long-term follow-up of the HEBE trial showed that increase in LVEDV was lower in the BMMC group. This study supports the long-term safety of intracoronary BMMC therapy. However, major clinical cardiovascular adverse events were significantly more frequent in the PBMC group.
Trial registration number The Netherlands Trial Register #NTR166 (http:// www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).
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INTRODUCTION
The effect of intracoronary infusion of mononuclear bone marrow mono nuclear cells (BMMCs) after acute myocardial infarction (AMI) in patients has been analysed in the past,1–3 with a moderate positive effect of BMMC treatment on LV function at short-term
follow-up.
Data regarding LV function at the long term are scarce and contradicting.4–9 Some
studies demonstrated a sustained positive or neutral effect at long term; another study had a transient positive effect and one study even had a neutral effect on short term and positive effect on the long term. Long-term clinical outcomes are essential for further evaluation of the efficacy of BMMC therapy after AMI, as currently, intracoronary BMMC therapy is used in research setting only and a large randomised controlled trial with a primary clinical endpoint is awaited.
The HEBE trial was a multicentre, randomised, open trial with blinded evaluation of endpoints of which the details of the design and main results have been published previously.10,11 Briefly, 200 patients with first ST-segment elevation myocardial infarction
treated with primary percutaneous coronary intervention (PCI) were enrolled in this study. After cardiac MRI (CMR), on day 2–7, patients were randomly assigned in a 1:1:1 ratio to either intracoronary infusion of autologous mononuclear BMMCs (n=69), intracoronary infusion of peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (without placebo infusion) (n=65). There were no significant differences between the two treatment groups and the control group. The HEBE trial included 3 treatment groups. Because the paracrine function of the injected cells is considered as an important mechanism and all mononuclear cells are capable of releasing vast amounts of growth factors and cytokines, it has been suggested that the potential beneficial effects can be attributed to the combined effects of all infused mononuclear cells, rather than the progenitor cell subpopulation. These considerations constituted the rationale for the third randomisation arm (PBMC) in our trial. Here, we evaluated the 5-year long-term clinical events follow-up and a 2-year CMR follow-up to assess effects on regional and global LV functions.
METHODS
As described previously, we estimated the enrolment of 60 patients in each study group to achieve a power of 90%, with a two-sided significance level of 0.05, to detect a 6% difference in change in global LVEF between active treatment and control, assuming a SD of 10%. It was assumed that up to 10% of patients would not have paired CMR studies and, therefore, a total of 200 patients were required.10,11 Cell harvesting in the
marrow (60 mL) was aspirated from the iliac crest under local anaesthesia. In the PBMC group, 150 mL of venous blood was collected. BMMCs or PBMCs were isolated by density gradient centrifugation, and 15 mL of cell suspension was used for intracoronary infusion.
In the bone marrow group, 3 patients did not have intracoronary infusion; in the peripheral blood group, 1 patient refused intracoronary infusion. The 3 groups were comparable with respect to baseline characteristics (table 1). Overall, the mean age was 56±9 years and 85% of the patients were men. At discharge, 95% were treated with β-blockers, 99% with statins and 93% with angiotensin-converting-enzyme or angiotensin inhibitors. There was no significant difference between the two treatment groups and the control group regarding the primary end point, namely the change in regional myocardial function in dysfunctional segments at 4 months relative to baseline, based on segmental analysis as measured by CMR. Also, no significant differences in the secondary endpoints of change in LVEF, volumes, mass and infarct size were observed. Furthermore, the 3 groups had similar rates of clinical events at 4 months follow-up. After 4 months, patients were contacted for additional informed consent for CMR at 2 years of follow-up and clinical follow-up at 5 years.
Table 1. Baseline characteristics of the HEBE trial
Characteristic BMMC group (n=69) PBMC group (n=66) Control Group (n=65) Age (years) 56±9 57±9 55±10 Male gender 58 (84%) 56 (85%) 56 (86%) Diabetes mellitus 3 (4%) 7 (11%) 2 (3%) Known hypertension 27 (39%) 13 (20%) 17 (26%)
Family history of coronary heart disease 33 (48%) 30 (45%) 33 (51%)
Hypercholesterolemia 17 (25%) 14 (21%) 15 (23%)
Current cigarette smoking 37 (54%) 31 (47%) 37 (57%) Infarct Related Artery
Left anterior descending artery 42 (61%) 46 (70%) 40 (62%)
Left circumflex artery 14 (20%) 5 (8%) 5 (8%)
Right coronary artery 13 (19%) 15 (23%) 20 (31%)
Multivessel disease 12 (17%) 21 (32%) 16 (25%)
BMMC=mononuclear bone marrow cells; PBMC=peripheral blood mononuclear cells Data previously published in Eur Heart J 2011;32:1736-47.
Cardiac MRI
Patients were studied using a clinical magnetic resonance scanner (Siemens, Erlangen, Germany; Philips, Best, The Netherlands; GE Healthcare, Buckinghamshire, UK). The
11
CMR protocol at 24 months was similar to the CMR protocol at baseline and 4 months,with the exception that no contrast medium was administrated. In short, contiguous short-axis slices were acquired every 10 mm covering the whole LV using a cine retrospectively ECG-gated segmented steady state free precession pulse sequence, with image parameters identical to the baseline and follow-up scan at 4 months. LV volumes and mass were measured on the cine images and indexed for body-surface area. LVEF was calculated.
For analysis of regional myocardial function, each short-axis slice was divided into 12 equi-angular segments to calculate wall thickening (in mm) of each segment by subtracting end-diastolic from end-systolic wall thickness. Myocardial segments were considered dysfunctional if segmental wall thickening was <3 mm. Improved wall thickening of a segment at follow-up was defined as >1.5 mm improvement in segmental wall thickening as compared with baseline and complete recovery was defined as segmental wall thickening ≥3.0 mm at follow-up.
All CMR analyses were performed in a core laboratory blinded to treatment allocation using a standardised protocol. Both baseline and 4-month follow-up scans were used to match all 3 studies for slice position using anatomic landmarks, such as papillary muscles and RV insertion sites.
Clinical events
To assess clinical status and adverse events, patients were seen at the outpatient clinic at 1, 4, 12, 24 and 60 months after randomisation. At 36 and 48 months, clinical follow-up was performed via telephone contact. All potential outcome events were recorded. If a patient could not be contacted, information was obtained from the general practitioner, treating cardiologist or hospital records. Data were censored at 5 years (1825 days) of follow-up or at the date of last contact. All new events occurring after previous reported data were adjudicated by a clinical event committee blinded to treatment allocation.
Statistical analysis
All analyses were performed on the basis of the intention-to-treat principle. Categorical data are presented as frequencies (percentage) and continuous data as mean ± SD. The analysis consisted of separate comparisons of the endpoints between the two active treatment groups and control. For the comparison of changes in CMR variables between groups, analysis of covariance was used including treatment group as the main factor and each baseline variable as a covariate. Safety of BMC administration was analysed using pre-specified clinical endpoints and included major adverse cardiovascular events defined as death, re-hospitalisation for heart failure and recurrent myocardial infarction. Cumulative event rates were assessed by the Kaplan–Meier method and compared
using a log-rank test. Follow-up was censored at the date of last contact or at 5 years, whichever came first. If the patient was lost to follow-up, censoring was done at the date of last clinical follow-up.
All p values are two-sided and statistical significance was set at p<0.05. Statistical analysis was done with the Statistical Package for Social Sciences software (SPSS V.19.0 for Windows).
RESUlTS
Of the 200 patients originally enrolled in the HEBE study, at 24 months one had withdrawn the informed consent, three had died, three patients did not consent to additional long-term follow-up and three patients were lost to follow-up. At 24 months, 19 patients had clinical follow-up but did not undergo CMR because of implantable cardioverter-defibrillator implantation (n=8), pacemaker implantation (n=1) or because they refused (n=10). In 12 patients the CMR scan was of poor quality due to breathing or triggering artefacts, or it was not possible to match with the baseline and 4-month studies, and therefore the patients were excluded from the analysis by the core lab (see figure 1). During long-term follow-up, 12 patients were lost to follow-up at 60 months.
lV function, volumes and infarct size
Paired cine CMR images for functional analyses were available for 59 patients in the BMMC group, 48 in the PBMC group and 52 in the control group. At 24 months, 45.0±26.3% of the dysfunctional segments showed improved segmental wall thickening in patients treated with BMMCs, compared with 52.3±22.6% in the control group (p=0.14). Patients treated with PBMCs showed less improvement of dysfunctional segments at 24 months of follow-up compared with control (42.5 ±20.7%, p=0.03; table 2).
Improvement of LVEF was 4.2±8.6% in the BMMC group, 3.0±8.3% in the PBMC group as compared with 4.0±8.6% in the control group (p=0.37 and p=0.17, respectively). Patients treated with intracoronary BMMC therapy had less increase in LV end diastolic volume (LVEDV) (3.5±16.9 mL/m2) as compared with controls (11.2±19.8 mL/m2,
p=0.03). Moreover, the BMMC group showed a trend for less increase in LV end systolic volume (LVESV) (−1.8±15.0 mL/m2) as compared with controls (3.0±16.3 mL/m2,
p=0.07). There were no other significant differences in the changes in LV volumes between the BMMC, PBMC and control group (table 2).
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Clinical outcome
At 5 years of follow-up, 88% were treated with β-blockers, 96% with statins and 89% with angiotensin-converting-enzyme or angiotensin inhibitors. There was no difference in medicine use in the treatment arms. Six patients in the BMMC group were classified as New York Heart Association (NYHA) Functional Classification class II and one patient as class III, compared with three patients in the control group with NYHA class II. All other patients were classified as NYHA class 1. In the PBMC group, 5 patients were classified as NYHA class II and 1 patient as class III. Two patients in the BMMC and two patients in the control group suffered from angina symptoms at 5 years of follow-up; one patient Canadian Cardiovascular Society (CCS) class 1 and one patient CCS class 2 in both treatment arms. One patient in the PBMC group suffered from angina symptoms
Figure 1: Study flow chart
BMMC=mononuclear bone marrow cells; CMR= cardiac magnetic resonance imaging. PBMC=peripheral blood mononuclear cells STEMI= ST-segment elevation myocardial infarction
T
able 2.
Quantitati
ve measures of
regional and global left v
entricular function, v
olumes
, mass and infarct size by CMR.
BMMC g roup PBMC g roup Control g roup BMMC vs . control PBMC vs . control Anal ysis at 4 months Anal ysis at 24 months (n=67) (n=59) Δ vs . baseline (n=62) (n=48) Δ vs . baseline (n=60) (n=52) Δ vs . baseline p v alue p v alue
Dysfunctional segments Impro
vement at 4 months 38.6±24.7 36.8±20.9 42.4±18.7 0.33 0.14 Impro vement at 24 months 45.0±26.3 42.5±20.7 52.3±22.6 0.14 0.03
LV ejection fraction (%) Baseline
43.7±9.0 41.7±9.1 42.4±8.3 0.42 0.67 4 months 47.5±9.9 3.8±7.4 46.0±9.3 4.2±6.2 46.4±9.2 4.0±5.8 0.52 0.80 24 months 49.2±8.1 4.2±8.6 44.9±10.3 3.0±8.3 47.7±9.4 4.0±8.6 0.37 0.17 LV end-diastolic v olume (mL/m 2) Baseline 97.3±14.0 98.0±15.4 100.0±16.9 0.32 0.50 4 months 102.6±19.1 5.4±13.4 103.4±22.6 5.3±16.3 108.2±24.6 8.2±13.5 0.16 0.26 24 months 99.9±20.2 3.5±16.9 108.0±28.1 9.2±20.9 110.3±28.3 11.2±19.8 0.03 0.69 LV end-systolic v olume (mL/m 2) Baseline 55.4±14.5 57.8±15.9 58.1±15.1 0.31 0.93 4 months 54.9±19.5 -0.5±13.4 57.1±21.6 -0.7±14.4 59.3±21.7 1.2±11.7 0.23 0.58 24 months 51.8±17.4 -1.8±15.0 61.3±26.4 3.3±18.8 59.1±23.8 3.0±16.3 0.07 0.66 BMMC=monon
uclear bone mar
ro
w cells; PBMC=peripheral blood monon
uclear cells
Baseline and 4 month L
V function pre viousl y published in Eur Hear t J 2011; 32 :1736-47.
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(CCS class 1). These differences in NYHA classifications and CCS classifications wereall non-significant.
During 5 years of follow-up, six patients assigned to the PBMC group died, compared with two patients in the control group (p=0.27). Ten patients treated with PBMC therapy had a recurrent myocardial infarction, compared with one in the control group (p=0.009). Three recurrent myocardial infarctions occurred during cell infusion. Of the remaining seven other recurrent myocardial infarctions, six were in the same vessel as the infarct related artery.
Eight patients in the BMMC group had a target lesion revascularisation, seven in the PBMC group and six in the control group (respectively, p=0.78 and 1.00). Table 3 summarises all clinical events from randomisation to 60-month follow-up. The combined endpoint of death and hospitalisation for heart failure was non-significantly more frequent in the control group compared with the BMMC group (n=4 vs n=1, p=0.20). Figure 2 shows the Kaplan–Meier survival curves for the composite of death or recurrent myocardial infarction of all three groups. The composite endpoint of death, recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008).
Table 3. Adverse events and clinical outcomes from randomization to 5 years of follow-up
Event BMMC (n=65) PBMC (n=63) Control Group (n=60) BMMC vs. control PBMC vs. control
At 60 months follow-up p value p value
Death 1 6 2 0.61 0.27
Recurrent myocardial infarction 1 10 1 1.00 0.009
Related to cell infusion procedure 0 3 –
Revascularization 17 15 13 0.68 0.83
Target lesion revascularization 8 7 6 0.78 1.00 Target vessel, nontarget lesion revascularization 12 9 8 0.47 1.00 Nontarget vessel revascularization 5 8 6 0.76 0.78 Documented ventricular arrhythmia treated by ICD 0 1 1 0.49 1.00
Hospitalization for heart failure 0 2 3 0.11 0.68
Hospitalization for chest pain 8 7 6 0.78 1.00
Stroke 1 2 0 1.00 0.50
Composite of death or recurrent myocardial
infarction 2 14 3 0.67 0.008
Composite of death or hospitalization for heart
failure 1 6 4 0.20 0.74
Composite of death, recurrent myocardial infarction
or hospitalization for heart failure 2 15 5 0.26 0.03
Data are number of patients; in composite endpoints multiple events in one patient are possible . BMMC=mononuclear bone marrow cells; PBMC=peripheral blood mononuclear cells
DISCUSSION
The present analysis confirms and extends our previous reports as we could not demonstrate a beneficial effect of intracoronary delivery of mononuclear cells from bone marrow or peripheral blood on regional and global systolic myocardial function at 2 years of follow-up in patients treated with primary PCI. Nevertheless, we observed that the increase in LVEDV was lower in the BMMC group. No late effects were observed in the BMMC group compared with controls, with comparable increments in the outcomes death and recurrent myocardial infarction up to 5 years of follow-up. The composite endpoint of death, recurrent myocardial infarction was significantly higher in the PBMC group compared with controls.
We previously demonstrated that of the 22 randomised controlled trials12 assessing
intracoronary bone marrow cell therapy after AMI, only 7 included long-term follow-up, defined as longer than 1 year after AMI. The REPAIR AMI trial13 and 2 other
studies, conducted by Cao et al4 and Plewka et al,14 demonstrated more improvement
Figure 2: The Kaplan-Meier curves for the composite of death or recurrent myocardial infarction
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in LV function after intracoronary BMMC therapy compared with controls at thetime of primary endpoint assessment, between 3 and 6 months. In these three studies this effect remained significant in favour of intracoronary cell therapy at 24,5 484 and
60 months6 after AMI. The BOOST trial demonstrated a benefit for patients treated
with intracoronary BMMC therapy compared with controls at 6 months of follow-up.15
However, this positive effect was no longer significant after 60 months.7 This has been
explained by a catch up phenomenon in the control group, suggesting that bone marrow cell therapy may, in fact, accelerate the post-AMI functional recovery, but that this effect is transient.
The study conducted by Penicka et al was prematurely ended due to futility and serious adverse events in the BMMC group.16 However, the authors demonstrated that BMMC
infusion in patients with AMI was associated with a significant improvement of global myocardial function during 24 months of follow-up compared with standard therapy.8
In the ASTAMI trial17 and the study conducted by Wohrle et al,18 intracoronary infusion
of mononuclear cells did not improve global LV function at the primary endpoint, as well as after 3 years of observation.9,19 These data are in line with our observations in the
HEBE trial.
We did find that the increase in LVEDV was lower in the BMMC group, with a trend for less increase in LVESV suggesting a long-term beneficial effect on adverse LV remodelling after AMI. The acute loss of myocardium results in an abrupt increase in loading conditions that induces a remodelling involving the infarcted border zone and remote non-infarcted myocardium. It has been postulated that intracoronary cell therapy, might specifically benefit the remote non-infarcted myocardium. Although this finding is interesting, in all CMR endpoints there were no differences compared with controls. Therefore we cannot exclude that this finding is due to chance and multiple testing. Finally, several postulated safety issues about intracoronary cell therapy have been raised. We have found low rates of adverse events, with no differences between BMMC group and controls. This is reassuring in terms of safety. Although the study is not powered to detect differences in clinical endpoints, long-term data from this study and others establish safety of intracoronary BMMC therapy. The combined endpoint of death and hospitalisation for heart failure was in the REPAIR-AMI trial, (non-significantly) more frequent in the placebo compared with the BMMC group (n=19 vs n=10 events, p=0.10) during the 5 years of follow-up.5 Unfortunately, we could not confirm these beneficial
effects in the HEBE trial.
We did demonstrate that long-term clinical follow-up is worse in patients treated with PBMC. Although these findings could be a matter of chance, it cannot be fully excluded
that PBMC infusion in the acute phase has aggravated underlying atherosclerotic disease leading to an increase in coronary ischaemic events. The events occurred during long-term follow-up, suggesting it is rather the progression of atherosclerosis than the acute effect of intracoronary infusion of PBMCs. Some small studies using granulocyte-colony stimulating factor or granulocyte-macrophage colony-stimulating factor suggested that an increase in the number of circulating leucocytes is related to plaque destabilisation.20,21
Our data do not support further research assessing the effect of local PBMC infusion. Limitations of this long-term study follow-up include a more than 10% loss of CMR follow-up at 24 months. However, overall loss of clinical follow-up at 60 months was low. Second, the original protocol did not include a pre-specified statistical plan for the 5 years of analysis, as the 2-year and 5-year follow-up were later added to the study protocol. Lastly, the HEBE study was, due to the ethical reasons, a non-blinded study with no true placebo control. Although there was a blinded evaluation of all endpoints, we cannot exclude the occurrence of potential biases.
In conclusion, we did not show a beneficial effect on clinical outcomes of intracoronary delivery BMMC compared with controls, with comparable increments in the outcomes death and recurrent myocardial infarction up to 5 years of follow-up. There was a significantly worse clinical outcome in patients treated with PBMC during 5 years of follow-up.
Acknowledgments
We thank all the investigators and coordinators of the HEBE trial and all the medical and nursing staff who made the trial possible. The complete list of investigators has been published previously.10
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