Cell Therapy Fails to Improve on CABG Results

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Save for some minor improvements in scar size and regional perfusion, bone marrow stem cells (BMCs) showed little positive impact on symptoms in patients with impaired left ventricular ejection fraction (LVEF) undergoing coronary artery bypass graft (CABG) surgery. Findings from the randomized trial were published online February 3, 2014, ahead of print in the European Heart Journal.

Researchers led by Christof Stamm, MD, of the Berlin-Brandenburg Center for Regenerative Therapies (Berlin, Germany), randomized 60 CABG patients with reduced global LVEF (< 35%) to intramyocardial injection of autologous CD133+ BMCs (n = 30) or placebo (n = 30).

On 6-month MRI (available in 48 patients), the primary endpoint of LVEF at rest was similar between groups, as were LV end diastolic diameter (LVEDD) and LV end diastolic volume (LVEDV, table 1).

Table 1. 6-Month Outcomes

Serious adverse events were equivalent between the 2 groups, with 13 in the placebo group and 12 in the BMC group.

Differences in Perfusion Noted

The proportions of LV myocardial segments with changes in perfusion deficit after surgery were different between groups. In the placebo group, perfusion deficit at rest was unchanged in 19% of all analyzed segments, better in 2%, and worse in 7%. In the BMC group, the perfusion deficit was unchanged in 15% (P = 0.2 vs placebo), improved in 9% (OR 4.0; 95% CI 1.6-9.8; P = 0.001), and worse in 1% of all analyzed segments (OR 0.2; 95% CI 0.07-0.05; P = 0.0007).

However, perfusion improvement in the BMC group did not always correlate with the location of the cell injection. Scar mass showed modest improvement in BMC patients, decreasing by 2.2 ± 5g (P = 0.05) while remaining unchanged in the placebo group (0.3 ± 4g; P = 0.7). In relation to the preoperative measurements, scar mass decreased by 9.7% in BMC patients and 0.6% in placebo patients (P = 0.1 for intergroup comparison). The difference between groups in the change in scar mass at follow-up was 2.0 g (95% CI -1.1 to 5.0; P = 0.2).

Most global LV function and dimension parameters improved after CABG irrespective of group assignment, but there were no significant differences at follow-up. For instance, with regard to regional contractility there were no differences in average 2D strain between groups preoperatively or at follow-up. Interestingly, when speckle-tracking echocardiography data were stratified according to location of the area of interest, a tendency was observed toward more improvement of regional LV function in patients with posterior or inferior infarction and BMC injection that was not apparent in the placebo group (P = 0.1 for group effect).  When the proportions of segments with improved longitudinal strain were compared between groups, regional contractile function recovery was improved in the BMC group at 3 months (OR 2.2; 95% CI 1.1-4.6; P = 0.03) but not at 6 months (P = 0.4). In fact, regional contractile function recovered in BMC patients only when the area of interest was posterior or inferior (P = 0.02 for localization effect). However, there was no correlation between area of interest location and LVEF or the change in global LV function at 6 months.

In 50 patients who underwent exercise testing, 6-month follow-up testing for V0_2max was similar between the placebo and BMC groups (14.4 ± 4.3 vs 14.9 ± 6 mL/min/kg; P = 0.7), as was VE/VC0₂ slope (31.5 ± 6.8 vs 31.3 ± 5.6; P = 0.9).

No Difference in Walk Test

In addition, change from preoperative levels of the 6-minute walk test were also similar between the placebo and BMC groups (28.7 m vs -2.3 m; P = 0.3). The majority of patients had fewer heart failure symptoms and angina at 6-month follow-up. However, the proportions of patients in the different NYHA classes revealed between-group differences, suggesting that NYHA class had improved more in the placebo group at 6 months than in the BMC group (P = 0.004). The authors call this finding, “difficult to explain.” For Canadian Cardiovascular Score class, this was not the case (P = 0.2).

Quality of life as assessed by the Minnesota Living with Heart Failure Score at 6 months was also similar between the placebo and BMC groups (12.7 vs 2.4; P = 0.1 for interaction).

In an email, Warren Sherman, MD, of Columbia University Medical Center (New York, NY), told TCTMD he was unsurprised by the findings, especially “given the mixed population of patients studied, which, despite the important requirement of having reduced LV systolic function (EF < 35%), contained those with both CHF and angina (more of the latter in the placebo group). Moreover, the range of time from last MI was quite large, up to 17- 28 years.”

The authors note that they conducted a similar trial which showed positive results with intramyocardial BMC infusion. Nevertheless, “the most significant aspect of all studies using this technique is their size,” Dr. Sherman said. “All published series have been small, including the present study.”

 He was still encouraged by some aspects of the study, however, especially the perfusion findings.

Overall, despite some improvements in scar size and regional perfusion, the authors conclude that “intra-myocardial injection of CD133+ BMC has no effect on global LV function and clinical symptoms. Improvements in regional myocardial function are only detectable in patients with posterior infarction, probably because the interventricular septum after anterior infarction is not accessible by trans-epicardial injection.”

Study Details

Three of the patients were female, and the mean age was 62.7 years in the placebo group and 61.9 years in the BMC group. Average LVEF was 26.2%, with a last documented MI less than 3 months before CABG in 9 patients in each group.

Source:

Nasseri BA, Ebell W, Dandel M, et al. Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur Heart J. 2014;Epub ahead of print.

Disclosures:

• The study was supported in part by Miltenyi Biotec and by the German Bundesministerium für Bildung und Forschung.
• Dr. Stamm reports receiving lecture fees from Miltenyi Biotec.
• Dr. Sherman reports no relevant conflicts of interest.

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