Shock & awe: Pretreatment plus cell therapy may benefit some HF patients

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 - clinical trial

Left ventricular ejection fraction (LVEF) improved in patients with postinfarction heart failure (HF) who received a shock-wave facilitated infusion of bone marrow-derived cells in a small randomized clinical trial. The improvement at four months was modest but significant, according to CELLWAVE trial researchers.

The study was published April 17 in the Journal of the American Medical Association.

“We have recently shown that extracorporeal application of focused low-energy shock waves increases the tissue expression of chemoattractants such as [chemokine] SDF-1 and vascular endothelial growth factor in the target tissues,” wrote Birgit Assmus, MD, of the Institute of Cardiovascular Regeneration at Goethe University in Frankfurt, Germany, and colleagues. “Our preclinical studies demonstrated that shock wave-induced local up-regulation of these chemoattractants resulted in significantly enhanced homing of applied cells, which translated into improved neovascularization of chronically ischemic tissue.”

CELLWAVE, a double-blind randomized controlled phase 1-2 clinical trial, was designed to determine whether a pretreatment of cardiac shock waves followed by intracoronary administration of autologous bone marrow-derived mononuclear cells (BMCs) in patients with chronic postinfarction heart failure would improve recovery of LVEF. The primary endpoint was improvement in global LVEF on angiography at four-months follow-up.

Patients first were randomized between 2006 and 2011 to three groups: low-dose shock-wave pretreatment (42 patients), high-dose shock-wave pretreatment (40 patients) and sham (placebo) shock-wave pretreatment (21 patients). The low-dose and high-dose groups then were randomized again to receive either BMCs or a placebo infusion after 24 hours. Everyone in the sham group received BMCs after 24 hours. The baseline LVEF did not differ significantly among all groups.  

At four months:

  • There was no change in LVEF in either of the low-dose and high-dose shock wave plus placebo infused groups;
  • There was no significant change in LVEF in the sham pretreatment plus BMCs group, and
  • There was a significant improvement in LVEF in patients who received either low-dose or high-dose pretreatment plus BMCs.

The researchers found an improvement in global LVEF of 3.2 percent in the low-dose/high-dose plus BMCs group compared with the shock wave and placebo group. LVEF improved in 27 of the 29 patients who received shock waves plus BMCs; in 18 of 28 patients who received shock waves and placebo; and nine of 14 patients in the sham shock wave and BMCs group.

Serial magnetic resonance imaging (MRI) in 38 patients found that the wall thickening of the infarcted segments improved significantly in those treated with shock waves and BMCs (8.3 percent to 11.9 percent) compared with shock waves and placebo (8.5 percent to 8.9 percent) and to sham shock waves and BMCs (5.1 percent to 9 percent).

Scar mass decreased significantly only in the shock waves/BMCs group. The overall occurrence of major adverse cardiac events also was less frequent in that group compared with the others.

The low-dose and high-dose shock wave plus placebo groups also had no improvement in heart failure status at four months while the high-dose plus BMCs group had an absolute -0.4 reduction in New York Heart Association class.

“The results demonstrate that shock wave-facilitated infusion of BMCs beneficially affects global and regional left ventricular contractile function and may reduce adverse clinical events in these chronically ill patients,” wrote Assmus et al.

They noted the improvement associated with shock-wave pretreatment followed by BMCs was modest but significant and was in line with the degree of improvement seen in other established therapies in this patient population.

“Moreover, MRI revealed a selective increase in infarct wall thickening and a measurable reduction in infarct size in the shock wave-BMCs group. It is possible that, with time, these improvements could contribute to reversal of the adverse remodeling that commonly follows myocardial infarction,” they suggested.

The researchers added that MRI was not possible in patients with implanted devices, though, “which would have precluded left ventricular analysis in half of our patient population.” They concluded that the benefits seen in CELLWAVE needed to be confirmed in a larger clinical trial.