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Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial.

ABSTRACT: For the last decade continuous efforts have been made to translate regenerative cell therapy protocols in the cardiovascular field from 'bench to bedside'. Successful clinical introduction, supporting safety, and feasibility of this new therapeutic approach, led to the initiation of the German, Phase III, multicenter trial - termed the PERFECT trial (ClinicalTrials.gov Identifier: NCT00950274), in order to evaluate the efficacy of surgical cardiac cell therapy on left ventricular function.The PERFECT trial has been designed as a prospective, randomized, double-blind, placebo controlled, multicenter trial, analyzing the effect of intramyocardial CD 133(+) bone marrow stem cell injection in combination with coronary artery bypass grafting on postoperative left ventricular function. The trial includes patients aged between 18 and 79?years presenting with a coronary disease with indication for surgical revascularization and reduced global left ventricular ejection fraction as assessed by cardiac magnet resonance imaging. The included patients are treated in the chronic phase of ischemic cardiomyopathy after previous myocardial infarction.Patients undergoing coronary artery bypass grafting in combination with intramyocardial CD133+ cell injection will have a higher LV ejection fraction than patient who undergo CABG alone, measured 6?months after the operation.ClinicalTrials.gov Identifier: NCT00950274.

SUBMITTER: Donndorf P

PROVIDER: S-EPMC3419083 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial.

Donndorf Peter P Kaminski Alexander A Tiedemann Gudrun G Kundt Guenther G Steinhoff Gustav G

Trials 20120702

<h4>Background</h4>For the last decade continuous efforts have been made to translate regenerative cell therapy protocols in the cardiovascular field from 'bench to bedside'. Successful clinical introduction, supporting safety, and feasibility of this new therapeutic approach, led to the initiation of the German, Phase III, multicenter trial - termed the PERFECT trial (ClinicalTrials.gov Identifier: NCT00950274), in order to evaluate the efficacy of surgical cardiac cell therapy on left ventricu ...[more]

PMID: 22747980

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Project description:Advances in modern medicine have led to people living longer and healthier lives. Frailty is an emerging concept in medicine yet to be explored as a risk factor in cardiac surgery. When it comes to CABG surgery, randomized controlled clinical trials have primarily focused on low-risk (ROOBY, CORONARY), elevated-risk (GOPCABE) or high-risk patients (BBS), but not on frail patients. Therefore, we believe that off-pump CABG could be an important technique in patients with limited functional capacity to respond to surgical stress. In this study, the authors introduce the new national, multicenter, randomized, controlled trial "FRAGILE", to be developed in the main cardiac surgery centers of Brazil, to clarify the potential benefit of off-pump CABG in frail patients.FRAGILE is a two-arm, parallel-group, multicentre, individually randomized (1:1) controlled trial which will enroll 630 patients with blinded outcome assessment (at 30 days, 6 months, 1 year, 2 years and 3 years), which aims to compare adverse cardiac and cerebrovascular events after off-pump versus on-pump CABG in pre-frail and frail patients. Primary outcomes will be all-cause mortality, acute myocardial infarction, cardiac arrest with successful resuscitation, low cardiac output syndrome/cardiogenic shock, stroke, and coronary reintervention. Secondary outcomes will be major adverse cardiac and cerebrovascular events, operative time, mechanical ventilation time, hyperdynamic shock, new onset of atrial fibrillation, renal replacement therapy, reoperation for bleeding, pneumonia, length of stay in intensive care unit, length of stay in hospital, number of units of blood transfused, graft patency, rate of complete revascularization, neurobehavioral outcomes after cardiac surgery, quality of life after cardiac surgery and costs.FRAGILE trial will determine whether off-pump CABG is superior to conventional on-pump CABG in the surgical treatment of pre-frail and frail patients.ClinicalTrials.gov, ID: NCT02338947. Registered on August 29th 2014; last updated on March 21st 2016.

Project description:BackgroundProlonged or excessive bleeding after cardiac surgery can lead to a broad spectrum of secondary complications. One of the underlying causes is incomplete wound drainage, with subsequent accumulation of blood and clots in the pericardium. We developed the continuous postoperative pericardial flushing (CPPF) therapy to improve wound drainage and reduce postoperative blood loss and bleeding-related complications after cardiac surgery. This study compared CPPF to standard care in patients after coronary artery bypass grafting (CABG).MethodsThis is a single center, open label, randomized trial that enrolled patients at the Amsterdam UMC, location AMC, Amsterdam, the Netherlands. The study was registered at the 'Netherlands Trial Register', study identifier NTR5200 [1]. Adults undergoing CABG were randomly assigned to receive CPPF therapy or standard care, participants and investigators were not masked to group assignment. The primary end point was postoperative blood loss in the first 12-hours after surgery.FindingsBetween the January 15, 2014 and the March 13, 2017, 169 patients were enrolled and assigned to CPPF therapy (study group; n = 83) or standard care (control group; n = 86). CPPF reduced postoperative blood loss when compared to standard care (median differences -385 ml, reduction 76% p=≤0.001), with the remark that these results are overestimated due to a measurement error in part of the study group. None of patients in the study group required reoperation for non-surgical bleeding versus 3 (4%, 95% CI -0.4% to 7.0%) in the control group. None of the patients in the study group suffered from cardiac tamponade, versus 3 (4%, 95% CI -0,4% to 7.0%) in the control group. The incremental cost-effectiveness ratio was €116.513 (95% bootstrap CI €-882.068 to €+897.278).InterpretationThe use of CPPF therapy after CABG seems to reduce bleeding and bleeding related complications. With comparable costs and no improvement in Qualty of Life (QoL), cost consideration for the implementation of CPPF is not relevant. None of the patients in the study group required re-interventions for non-surgical bleeding or acute cardiac tamponade, which underlines the proof of concept of this novel therapy.FundingThis study was funded by ZonMw, the Netherlands organization for health research and development (project 837001405).

Project description:ImportanceIncentive spirometers (ISs) were developed to reduce atelectasis and are in widespread clinical use. However, without IS use adherence data, the effectiveness of IS cannot be determined.ObjectiveTo evaluate the effect of a use-tracking IS reminder on patient adherence and clinical outcomes following coronary artery bypass grafting (CABG) surgery.Design, setting, and participantsThis randomized clinical trial was conducted from June 5, 2017, to December 29, 2017, at a tertiary referral teaching hospital and included 212 patients who underwent CABG, of whom 160 participants were randomized (intent to treat), with 145 completing the study per protocol. Participants were stratified by surgical urgency (elective vs nonelective) and sex (men vs women).InterventionsA use-tracking, IS add-on device (SpiroTimer) with an integrated use reminder bell recorded and timestamped participants' inspiratory breaths. Patients were randomized by hourly reminder "bell on" (experimental group) or "bell off" (control group).Main outcomes and measuresIncentive spirometer use was recorded for the entire postoperative stay and compared between groups. Radiographic atelectasis severity (score, 0-10) was the primary clinical outcome. Secondary respiratory and nonrespiratory outcomes were also evaluated.ResultsA total of 145 per-protocol participants (112 men [77%]; mean age, 69 years [95% CI, 67-70]; 90 [62%] undergoing a nonelective procedure) were evaluated, with 74 (51.0%) in the bell off group and 71 (49.0%) in the bell on group. The baseline medical and motivation-to-recover characteristics of the 2 groups were similar. The mean number of daily inspiratory breaths was greater in bell on (35; 95% CI, 29-43 vs 17; 95% CI, 13-23; P < .001). The percentage of recorded hours with an inspiratory breath event was greater in bell on (58%; 95% CI, 51-65 vs 28%; 95% CI, 23-32; P < .001). Despite no differences in the first postoperative chest radiograph mean atelectasis severity scores (2.3; 95% CI, 2.0-2.6 vs 2.4; 95% CI, 2.2-2.7; P = .48), the mean atelectasis severity scores for the final chest radiographs conducted before discharge were significantly lower for bell on than bell off group (1.5; 95% CI, 1.3-1.8 vs 1.8; 95% CI, 1.6-2.1; P = .04). Of those with early postoperative fevers, fever duration was shorter for bell on (3.2 hours; 95% CI, 2.3-4.6 vs 5.2 hours; 95% CI, 3.9-7.0; P = .04). Having the bell turned on reduced noninvasive positive pressure ventilation use rates (37.2%; 95% CI, 24.1%-52.5% vs 19.2%; 95% CI, 10.2%-33.0%; P = .03) for participants undergoing nonelective procedures. Bell on reduced the median postoperative length of stay (7 days; 95% CI, 6-9 vs 6 days; 95% CI, 6-7; P = .048) and the intensive care unit length of stay for patients undergoing nonelective procedures (4 days; 95% CI, 3-5 vs 3 days; 95% CI, 3-4; P = .02). At 6 months, the bell off mortality rate was higher than bell on (9% vs 0%, P = .048) for participants undergoing nonelective procedures.Conclusions and relevanceThe incentive spirometer reminder improved patient adherence, atelectasis severity, early postoperative fever duration, noninvasive positive pressure ventilation use, ICU and length of stay, and 6-month mortality in certain patients. With the reminder, IS appears to be clinically effective when used appropriately.Trial registrationClinicalTrials.gov identifier: NCT02952027.

Project description:The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair.Multicentre, double-blinded, randomised placebo controlled trial.The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015.Post-infarction patients with chronic ischemia and reduced LVEF (25-50%).Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5-5×106 CD133+.Primary endpoint was delta (?) LVEF at 180days (d) compared to baseline measured in MRI.Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133+. Efficacy (n=58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p=0.001 (n=58). Treatment groups were not different in ?LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ?CD133+vs placebo +2.6%, p=0.4).Responders (R) classified by ?LVEF?5% after 180d were 60% of the patients (35/58) in both treatment groups. ?LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (?LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p=0.005) and thrombocytes (p=0.004) in contrast to increased Erythropoeitin (p=0.02), and SH2B3 mRNA expression (p=0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature.ClinicalTrials.govNCT00950274.

Project description:In severe coronary artery disease, coronary artery bypass grafting (CABG) surgery is indicated to re-establish an adequate blood supply to the ischemic myocardium. Effectiveness of CABG surgery for symptom relief and mortality decrease should therefore depend on bypass graft patency. As bypass using a left internal mammary artery (LIMA)-to-left anterior descending coronary artery (LAD) anastomosis allows the best results in terms of graft patency, we designed a new surgical technique using a saphenous vein graft as a venous bridge to distribute the LIMA flow to the cardiac anterolateral territory. This novel strategy could extend the patency benefits associated to the LIMA. Other potential benefits of this technique include easier surgical technique, possibility to use saphenous vein grafts as vein patch angioplasty, shorter saphenous vein grafts requirement and reduced or eliminated manipulations of the ascendant aorta (and associated stroke risk).Between July 2012 and 2016, 200 patients undergoing a primary isolated CABG surgery using cardiopulmonary bypass with a LAD bypass graft and at least another target on the anterolateral territory will be randomized (1:1) according to 1) the new composite strategy and 2) the conventional strategy with a LIMA-to-LAD anastomosis and revascularization of the other anterolateral target(s) with a separated aorto-coronary saphenous vein graft. The primary objective of the trial is to assess whether the composite strategy allows non-inferior anterolateral graft patency index (proportion of non-occluded CABGs out of the total number of CABGs) compared to the conventional technique. The primary outcome is the anterolateral graft patency index, evaluated at one year by 256-slice computed tomography angiography. Ten years of clinical follow-up is planned to assess clinical outcomes including death, myocardial infarction and need for revascularization.This non-inferiority trial has the potential to advance the adult cardiac surgery field, given the potential benefits associated with the composite grafting strategy.ClinicalTrials.gov: NCT01585285.

Dataset Information

Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial.

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Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial.

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