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This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34(+) cells would improve total exercise time (TET) and angina frequency in patients with refractory angina.IM administration of autologous CD34(+) cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials.RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34(+) administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months.The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34(+) cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34(+)]).Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910).

Rationale: A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function. Objective: Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options. Methods and Results: In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10 5 or 5×10 5 cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P =0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P =0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P =0.014; 12 months: 140±171 versus 58±146 seconds, P =0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients. Conclusions: Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10 5 cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

One of the aims of secondary prevention is to achieve plaque stabilization. This study sought to investigate the clinical consequences and predictive factors of the change in the type of plaque (CTP) as assessed by serial intracoronary ultrasound in type II diabetic patients with known coronary artery disease.237 segments (45 patients) from the DIABETES I, II, and III trials were included. Intracoronary ultrasound from motorized pullbacks (0.5mm/s) after index procedure and at 9-month angiographic follow-up was performed in the same coronary segment. Nontreated mild lesions (angiographic stenosis25%) with ≥0.5mm plaque thickening and ≥5mm of length assessed by intracoronary ultrasound were included. As different types of plaques may be encountered throughout a given coronary lesion, each study lesion was divided into 3 segments for serial quantitative and qualitative analyses. Statistical adjustment by multiple lesion segments per patient (generalized estimating equations method) was performed. A CTP was defined as any qualitative change in plaque type at follow-up. At 1-year follow-up, major adverse cardiac events - death, myocardial infarction and target vessel revascularization) - were recorded.A CTP was observed in 48 lesions (20.2%) and occurred more frequently (52.1%) in mixed plaques. Independent predictors of CTP were glycated hemoglobin levels (odds ratio [OR] 1.2; 95% confidence interval [CI] 1.01-1.5; P=.04); glycoprotein IIb-IIIa inhibitors (OR 0.3; 95% CI 0.1-0.7; P=.004) and statin administration (OR 0.3; 95% CI 0.1-0.8; P=.02). At 1-year follow-up CTP was associated with an increase in major adverse cardiac events rate (CTP 20.8% vs non-CTP 13.8%, P=.008; hazard ratio=1.9, 95% CI 1.3-1.9, P=.01).Qualitative changes in mild stenosis documented by intracoronary ultrasound in type II diabetics are associated with suboptimal secondary prevention and may have clinical consequences. Full English text available from: www.revespcardiol.org.

A predefined intravascular ultrasound (IVUS) substudy was performed to evaluate the vascular effects of sirolimus-eluting stent (SES) versus bare-metal stent (BMS).The Diabetes and Sirolimus-Eluting Stent (DIABETES) trial is a prospective, multicenter, randomized, controlled trial aimed at demonstrating the efficacy of the SES compared with BMS in diabetic patients.Serial intravascular ultrasound analyses were performed in 140 lesions (SES = 75; BMS = 65) immediately after stent implantation and at nine-month follow-up. Vessel, luminal, and stent mean areas and volumes were evaluated at both edges and within the stented segment. Qualitative assessment of residual dissections and stent apposition were also performed.Baseline clinical and angiographic characteristics were similar between groups. At 9 months, in-stent neointimal hyperplasia (NIH) mean area and volume were significantly reduced in the SES group (median NIH area 0.01 mm2 [0.0 to 0.1] vs. 2.0 mm2 [1.0 to 2.9] and median NIH volume 0.11 mm3 [0 to 2.1] vs. 35.3 mm3 [16.6 to 62.6]; both p0.0001). In the SES group, stent edges evidenced significant increase in lumen dimensions mainly due to significant increase in vessel volume, whereas those of the BMS group presented vessel shrinkage leading to significant lumen reduction. Late acquired incomplete stent apposition was observed in 11 lesions (14.7%) in the SES group and 0 in the BMS group (p = 0.001). At one year, no stent thromboses occurred in malapposed stents.The SES implantation effectively inhibits NIH in diabetic patients. The antirestenotic effect of SES is also appreciated at the stent edges. Late acquired stent malapposition is a frequent phenomenon in diabetic patients treated with SES.

As part of a randomized prospective study designed to investigate the restenosis process after percutaneous transluminal coronary angioplasty (PTCA), the relation between patient-related variables and restenosis rate was examined. A total of 722 patients had successful PTCA. Angiographic follow-up was scheduled for 6 +/- 2 months after the procedure and achieved in 510 patients (71%), yielding 598 lesions for analysis. The overall restenosis rate was 40%. The rate was higher in patients undergoing early restudy for a clinical event than in those undergoing routinely scheduled follow-up restudy (71 vs 22%, p less than 0.0001). Age, sex, cigarette smoking history, diabetes mellitus and history of previous myocardial infarction were not associated with restenosis rate. Angina duration and severity before PTCA were also unrelated to restenosis rate. In summary, these variables, many of which have been previously implicated in restenosis, were not found to be predictors of restenosis. The decision to perform PTCA in individual patients should not be negatively influenced by the presence of these factors.