MedWire - ESC (Munich, Germany), September 2, 2008: This Hotline Session on the fourth day of the European Society of Cardiology (ESC) Congress 2008 featured the presentation of several large clinical trials, including a study of myocardial regeneration by intracoronary infusion of stem cells in acute myocardial infarction (MI), and a Phase II evaluation of darapladib, an investigational compound with putative plaque-modifying properties. The main findings are summarized and discussed below.
REGENT: Stem cells in acute myocardial infarction
Dr. Michel Tendera, Medical University of Silesia, Katowice, PolandREGENT (Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction) was a randomized multicenter trial that studied the effect of intracoronary infusion of selected bone-marrow-derived stem cells in patients with acute MI and a reduced left ventricular ejection fraction (LVEF).
The study rationale was that acute MI induces mobilization of CD34+CXCR4+ cells, and that these circulating cells are enriched in early cardiac and endothelial markers. “CD34+CXCR4+ cells can migrate to the infarct area and are potentially useful for myocardial repair,” Dr. Tendera explained.
To test this hypothesis, 200 patients with acute anterior MI and LVEF ≤40% were enrolled and randomized to one of three groups:
- control (no cell therapy, n=40)
- unselected stem cells (n=80)
- selected CD34+CXCR4+ cells (n=80).
The average time between percutaneous coronary intervention and intracoronary cell infusion was 7 days.
The study’s primary endpoint was the change in LVEF and LV volumes as assessed with cardiac magnetic resonance imaging at 6 months.
Results showed that LVEF rose by 3% in both of the cell-therapy groups but was unchanged in the control group, Dr. Tendera revealed. The between-group difference was not statistically significant, however, and LV volumes changed by a similar magnitude in all three groups.
Interestingly, baseline LVEF was an independent predictor of a significant increase in LVEF after treatment, with the greatest response occurring in patients whose initial LVEF was below the median (37%). In this subgroup, LVEF rose from 29.5% to 34.5% with selected cell therapy and from 31% to 36% with unselected cells.
The study was not powered to detect differences in major clinical events. Nevertheless, at 6-month follow-up, the rate of major cardiovascular adverse events was low in all groups, indicating that cell therapy was safe.
“The improvement in LVEF in patients with severely depressed LV systolic function treated with both selected CD34+CXCR4+ cells and unselected bone-marrow-derived mononuclear cells warrants further study,” Dr. Tendera concluded.
Discussion
Dr. Helmut Drexler, University of Hannover, Germany
Dr. Drexler congratulated the REGENT trial investigators on “a wonderful job” in spite of the negative result. REGENT is the fifth completed trial of intracoronary stem cell infusion in acute MI, just two of which have been positive. He said that cell isolation procedures could explain the disappointing results: “Timing, cell preparation, and selection of cells including their biological activity appear to be crucial,” he remarked.
He also noted that the same amount of bone marrow was obtained from both cell-therapy groups. Therefore, both groups received the same total amount of CD34+CXCR4+ cells; the only difference was that the selected cells were diluted by other bone-marrow cells in the unselected-cell group.
“REGENT is a great effort and an excellently executed large cell-therapy trial indicating once again that bone marrow cell therapy post-MI is safe,” he stated. “Unfortunately the results are a mixed bag…. Cell therapy still has a long way to go.”
IBIS-2: Darapladib on coronary atheroscleroticplaqueDr. William Wijns, OLV Hospital Aalst, BelgiumIBIS-2 (Integrated Biomarker and Imaging Study-2) was a randomized placebo-controlled study that evaluated the impact of an investigational therapy, darapladib, on human coronary atherosclerotic plaque. Darapladib is a potent oral drug that selectively inhibits lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme secreted by leukocytes.
Lp-PLA2 is thought to be a key player in atherosclerosis, said Dr. Wijns, and is found in large amounts in the necrotic core of unstable atherosclerotic plaques. Inhibiting this enzyme might therefore modify the composition of atherosclerotic plaque, making it less prone to rupture.
This hypothesis was tested in IBIS-2, which enrolled 330 patients with chronic or acute coronary artery disease and randomized patients to receive darapladib 160 mg/day or placebo. The primary endpoint was plaque deformability, measured using intravascular ultrasound, after 12 months of treatment. This is an intermediate endpoint that is mechanistically related to plaque rupture, said Dr. Wijns. A coprimary endpoint was the change in high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation.
He then revealed the main result, which was that plaque deformability changed by a similar degree in both the darapladib and placebo groups, indicating no significant effect of therapy. However, plaque composition, a secondary endpoint, differed between the groups, with darapladib-treated patients showing a stabilization of the necrotic core volume compared with an increase in the placebo group. This effect of darapladib therapy on the necrotic core volume was consistent across patient subgroups, said Dr. Wijns.
In addition, darapladib therapy was associated with significant reductions in plasma Lp-PLA2 activity but did not affect levels of hs-CRP or low-density-lipoprotein cholesterol. Importantly, active treatment was not associated with an excess of adverse events.
“Darapladib halted necrotic core expansion when compared to standard care alone,” Dr. Wijns concluded. “The results confirm a pro-atherogenic role of Lp-PLA2… Chronic Lp-PLA2 inhibition may represent a novel approach for plaque stabilization.”
Discussion
Dr. Filippo Crea, Institute of Cardiology, Catholic University, Rome, ItalyThe IBIS-2 study was discussed by Dr. Crea, who was more cautious in interpreting the results. He said there was a clear need for new effective treatments to reduce cardiac events in patients with heart disease and agreed that Lp-PLA2 had a net proatherogenic effect. However, he said it had not yet been proven that the enzyme had a directly causal role in acute vascular events.
He said the IBIS-2 study had strengths including its innovative rationale, good design, and experienced investigators; on the downside, he questioned the choice of a non-validated surrogate as the primary endpoint.
“Darapladib failed to affect the two coprimary endpoints of the trial [coronary plaque deformability and hs-CRP],” he concluded. “Thus further studies using validated surrogate endpoints are appropriate before considering larger trials with clinical endpoints.”
