Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial

Background:

Small studies have yielded divergent results for administration of granulocyte colony-stimulating factor (G-CSF) after acute myocardial infarction. Adequately powered studies involving patients with at least moderate left ventricular dysfunction are lacking.

Methods:

Patients with left ventricular ejection fraction less than 45% after anterior-wall myocardial infarction were treated with G-CSF (10 μg/kg daily for 4 days) or placebo. After initial randomization of 86 patients, 41 in the placebo group and 39 in the G-CSF group completed 6-month follow-up and underwent measurement of left ventricular ejection fraction by radionuclide angiography.

Results:

Baseline and 6-week mean ejection fraction was similar for the G-CSF and placebo groups: 34.8% (95% confidence interval CI] 32.6%–37.0%) v. 36.4% (95% CI 33.5%–39.2%) at baseline and 39.8% (95% CI 36.2%–43.4%) v. 43.1% (95% CI 39.2%–47.0%) at 6 weeks. However, G-CSF therapy was associated with a lower ejection fraction at 6 months relative to placebo (40.8% 95% CI 37.4%–44.2%] v. 46.0% 95% CI 42.7%–44.3%]). Both groups had improved left ventricular function, but change in left ventricular ejection fraction was lower in patients treated with G-CSF than in those who received placebo (5.7 95% CI 3.4–8.1] percentage points v. 9.2 95% CI 6.3–12.1] percentage points). One or more of a composite of several major adverse cardiac events occurred in 8 patients (19%) within each group, with similar rates of target-vessel revascularization.

Interpretation:

In patients with moderate left ventricular dysfunction following anterior-wall infarction, G-CSF therapy was associated with a lower 6-month left ventricular ejection fraction but no increased risk of major adverse cardiac events. Future studies of G-CSF in patients with left ventricular dysfunction should be monitored closely for safety. Trial registration: ClinicalTrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT00394498","term_id":"NCT00394498"}}NCT00394498Rapid reperfusion therapy has become the standard treatment for ST-segment elevation myocardial infarction (STEMI), with congestive heart failure and left ventricular dysfunction continuing as the strongest predictors of higher long-term risk.¹ To date, no definitive therapies exist to regenerate myocardium following myocardial necrosis, and myocardial preservation is therefore the goal of STEMI care. Contemporary studies have suggested the possibility of myocardial regeneration by endogenous stem and progenitor cell populations, and preliminary clinical studies have hinted at potential benefit.^2,3 Studies investigating whether postinfarction myocardial function can be improved by enhancing stem cell–mediated repair are in progress ({"type":"clinical-trial","attrs":{"text":"NCT00936819","term_id":"NCT00936819"}}NCT00936819 and {"type":"clinical-trial","attrs":{"text":"NCT00984178","term_id":"NCT00984178"}}NCT00984178).Granulocyte colony-stimulating factor (G-CSF), an endogenously produced glycoprotein growth factor, when given in pharmacologic doses, stimulates mobilization of hematopoietic stem cells into the peripheral blood. Therapeutically, recombinant synthetic forms have been used to enhance recovery from neutropenia following chemotherapy and for mobilization of stem cells before hematopoietic stem cell transplant.⁴ Numerous small clinical studies have investigated the potential of G-CSF–induced mobilization of stem cells in the peri-infarction period to enhance left ventricular recovery, but they have yielded discordant results. However, meta-analyses have suggested benefit for left ventricular ejection fraction in subgroups who received G-CSF early after infarction or in patients whose left ventricular dysfunction was mild to moderate.^5,6 Larger trials are necessary because, in addition to mobilizing stem cells, G-CSF modulates intracellular signalling cascades within cardiomyocytes and can activate neutrophils, and several trials have been stopped early as a result of excessive in-stent restenosis and acute coronary syndromes in patients with coronary artery disease.^7–11 Animal data have similarly yielded discordant results, depending on the dose and timing of G-CSF.¹²To clarify the role of G-CSF in promoting left ventricular recovery after acute myocardial infarction, we performed an adequately powered randomized clinical trial in patients with moderate left ventricular dysfunction following anterior-wall STEMI.