Bone Marrow Stem Cells Not Effective Early or Late After AMI

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Intracoronary infusion of autologous bone marrow stem cells fails to improve left ventricular function regardless of how soon after ST-segment elevation myocardial infarction (STEMI) they are given, according to a study published online April 17, 2013, ahead of print in Circulation.

Results of the SWISS-AMI trial were initially presented November 6, 2012, at the American Heart Association Scientific Sessions in Los Angeles, CA.

Researchers led by Roberto Corti, MD, of University Hospital Zurich (Zurich, Switzerland), randomized 200 STEMI patients receiving primary PCI at 4 Swiss hospitals to 1 of 3 groups:

• Bone marrow stem cell intracoronary infusion 5 to 7 days post MI (early group; n = 66)
• Intracoronary infusion 3 to 4 weeks post MI (late group; n = 67)
• Optimal medical therapy (control group; n = 67)

Timing of Little Importance

At 4 months, the mean absolute global change in LVEF as assessed by cardiac MRI was -0.4% in controls, 1.8% in the early group, and 0.8% in the late group. Using an ANCOVA model to analyze for covariance, the estimated treatment effect averaged 1.25 for the early group (95% CI -1.83 to 4.32; P = 0.42 vs. controls) and 0.55 for the late group (95% CI -2.61 to 3.71; P = 0.73 vs. controls).

When both the early and late groups were combined, the estimated treatment effect for stem cell therapy was 0.85 (95% CI -1.75 to 3.44; P = 0.52 vs. controls).

Secondary endpoints were also similar between the control, early, and late groups, with the exception of LV end diastolic volume, which showed improvement in the late group vs. controls (P = 0.04).

Table 1. Secondary Endpoints at 4 Months

There was no difference in the frequency of serious adverse events at 4 months between the groups, including the combined composite endpoint (death, MI, revascularization, rehospitalization for heart failure) or any of the component endpoints in addition to stroke. Overall mortality was 2%, with no deaths in the control group, 1 death (1.7%) in the late group, and 3 deaths (4.6%) in the early group.

At 4 months, more than 75% of patients were in NYHA class I and more than 92% were in Canadian Cardiac Society class I, with no difference between groups.

Patients reperfused early (before median of 4.5 hours) did show a higher treatment effect from cell therapy, whether they were injected early (estimated treatment effect of 6.31; 95% CI 0.13-12.48; P = 0.046 vs. controls) or late (9.17; 95% CI 3.08-15.26; P = 0.004 vs. controls) after AMI.

Patients with higher nt-proBNP levels at baseline (above median 1,437 ng/L) also showed a greater treatment effect with cell therapy, whether they were injected early (7.1; 95% CI 1.00-13.20; P = 0.023 vs. controls) or late (9.02; 95% CI 2.24-15.79; P = 0.01 vs. controls) after AMI.

After adjustment for baseline LVEF, regression analysis failed to show any influence of cell-related parameters including total number of mononuclear cells, total number of CD34+ and CD133+ cells, or age on LVEF at 4 months.

Cell Therapy Cooling Down?

“Surprisingly, the results of our study do not confirm any significant improvement of global LV function at 4 months follow-up, neither with early (5-7 days) nor with late (3-4 weeks) application of [bone marrow stem cells] after a first and rather large AMI,” the researchers conclude, adding that “The results of the SWISS-AMI trial may further cool down the euphoria which initially accompanied application of progenitor-cell based research.”

They hypothesized that the improved treatment effect among patients with chest pain-to-reperfusion times below 4.5 hours may be due to lower transmurality or less microvascular obstruction after early reperfusion. “[W]e suggest that in patients with complete transmural scar, [bone marrow stem cell] treatment may be less beneficial,” they explain.

In an accompanying editorial, Jalees Rehman, MD, of the University of Illinois at Chicago (Chicago, IL), notes that the primary endpoint of SWISS-AMI, LVEF, is only a surrogate marker for clinically meaningful outcomes, which the trial was not powered to detect. In addition, the trial only lasted 4 months, whereas longer follow-up may have revealed some benefit from cell therapy.

Nevertheless, “the SWISS-AMI trial once again casts doubt on the idea that [bone marrow stem cell] infusions are beneficial for MI patients,” Dr. Rehman notes.

Field Still Moving Forward

In a telephone interview with TCTMD, Warren Sherman, MD, of Columbia University Medical Center (New York, NY), commented, “What is a bit more surprising [than the lack of effect of late cell therapy administration] is that the early administration group didn’t do better. That’s somewhat at odds with many of the studies that have been looked at.”

Still, he stressed that although the results of SWISS-AMI are negative, there have been other negative studies in the past, and they are in the minority. “It’s not going to alter what’s going on currently,” he noted, referring to the large European Bone Marrow Cells in Acute Myocardial Infarction (BAMI) cell therapy trial currently underway. “[SWISS-AMI] is a small, nonplacebo controlled study, and I don’t think had it appeared 5 years earlier that it would have altered the course of the field at the moment. The field needs a really good pivotal study behind it, and that’s starting now.”

Study Details

Overall, 92% of patients had anterior STEMI due to LAD occlusion. Median baseline LVEF at 6 days post MI was 37.4%. A total of 153 x 10⁶ nucleated cells were infused. Besides an impurity of granulocytes, the mononuclear fraction consisted mainly of lymphocytes and monocytes. There was no significant difference between the early and late groups except for a higher percentage of CD 34+ cells in the late group.

 

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Sources:
1. Sürder D, Manka R, Lo Cicero V, et al. Intracoronary injection of bone marrow derived mononuclear cells, early or late after acute myocardial infarction: Effects on global left ventricular function four months results of the SWISS-AMI trial. Circulation. 2013;Epub ahead of print.

2. Rehman J. Bone marrow tinctures for cardiovascular disease: Lost in translation. Circulation. 2013;Epub ahead of print.

 

 

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