Cardiopoietic Stem Cell Therapy in Heart Failure Bartunek, Jozef, MD, PhD; Behfar, Atta, MD, PhD; Dolatabadi, Dariouch, MD ...
Journal of the American College of Cardiology,
06/2013, Letnik:
61, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow–derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in ...patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail–based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. −15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238 ).
Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, ...hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium.
We randomly assigned 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina (on a scale from I to IV, with higher classes indicating greater limitations on physical activity owing to angina) and myocardial ischemia, who were not candidates for revascularization, to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months.
A total of 35% of the patients in the treatment group (18 of 52 patients), as compared with 15% of those in the control group (8 of 52), had an improvement of at least two CCS angina classes at 6 months (P=0.02). The device was also associated with improvement of at least one CCS angina class in 71% of the patients in the treatment group (37 of 52 patients), as compared with 42% of those in the control group (22 of 52) (P=0.003). Quality of life as assessed with the use of the Seattle Angina Questionnaire was significantly improved in the treatment group, as compared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P=0.03). There were no significant between-group differences in improvement in exercise time or in the mean change in the wall-motion index as assessed by means of dobutamine echocardiography. At 6 months, 1 patient in the treatment group had had a myocardial infarction; in the control group, 1 patient had died and 3 had had a myocardial infarction.
In this small clinical trial, implantation of the coronary-sinus reducing device was associated with significant improvement in symptoms and quality of life in patients with refractory angina who were not candidates for revascularization. (Funded by Neovasc; COSIRA ClinicalTrials.gov number, NCT01205893.).
Objectives This study sought to demonstrate the noninferiority of polymer-free amphilimus-eluting stents (Cre8, CID, Saluggia, Italy) versus permanent-polymer paclitaxel-eluting stents (Taxus ...Liberté, Boston Scientific, Natick, Massachusetts) in de novo percutaneous coronary intervention. Background Although the efficacy of the drug-eluting stent has been well established, the risk-benefit balance is still suboptimal, and the safety of polymers remains uncertain. Methods Patients undergoing percutaneous coronary intervention for de novo lesions were randomly assigned 1:1 to Cre8 or Taxus Liberté stents. Primary endpoint was 6-month angiographic in-stent late lumen loss (LLL) within a noninferiority scope. Six-month intravascular ultrasound was performed in 20% of the patients. All patients will be clinically followed up to 5 years. Results Out of 323 patients enrolled, 162 received Cre8 and 161 Taxus Liberté stents. In-stent LLL was significantly lower in Cre8 group (0.14 ± 0.36 mm vs. 0.34 ± 0.40 mm, p noninferiority <0.0001, p superiority <0.0001). Clinical endpoints (cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis) up to 12 months did not differ significantly between the groups. Conclusions The Cre8 stent in de novo lesions showed significantly lower in-stent LLL at 6 months than the Taxus Liberté stent did, with a trend toward better 12-month clinical safety and efficacy results. (International Randomized Comparison Between DES Limus Carbostent and Taxus Drug-Eluting Stents in the Treatment of De Novo Coronary Lesions NEXT; NCT01373502 )
The primary results of Arterial Revascularization Therapy Study reported a greater need for repeated revascularization after percutaneous coronary intervention with stenting (PCI). However, PCI was ...less expensive than coronary artery bypass grafting (CABG) and offered the same degree of protection against death, stroke, and myocardial infarction.
Patients with multivessel disease (n=1205) were randomly assigned to either CABG or PCI and followed up for up to 3 years. Survival rates without stroke or myocardial infarction were similar in each group at 1 year and 3 years (90.5% versus 91.4% for PCI versus CABG at 1 year and 87.2% versus 88.4% for PCI versus CABG at 3 years). However, the respective repeat revascularization rates were 21.2% and 26.7% at 1 and 3 years in patients allocated to PCI, compared with 3.8% and 6.6% in patients allocated to CABG (P<0.0001). Diabetes (P<0.0009) and maximal pressure for stent deployment (P<0.002) are the strongest independent predictors of events at 3 years after PCI, whereas left anterior descending coronary artery grafting (P<0.006) is the best predictor of event-free survival at 3 years after CABG. The incremental cost of surgery compared with PCI for an event-free patient was 19 257 at 1 year but decreased to 10 492 at 3 years. It remained at 142 391 at 3 years when revascularization procedures were excluded in the efficacy end point, however.
Three-year survival rates without stroke and myocardial infarction are identical in both groups, and the cost/benefit ratio of stenting is determined primarily by the increasing need for revascularization in the PCI group.
The DynamX Novolimus-Eluting Coronary Bioadaptor System ( DynamX ® Bioadaptor) has uncaging elements that disengage after the resorption of the polymer coating, aiming to restore vessel function in ...the treated segment and to avoid long-term adverse outcomes associated with the permanent caging of the coronary artery seen with conventional stenting.BackgroundThe DynamX Novolimus-Eluting Coronary Bioadaptor System ( DynamX ® Bioadaptor) has uncaging elements that disengage after the resorption of the polymer coating, aiming to restore vessel function in the treated segment and to avoid long-term adverse outcomes associated with the permanent caging of the coronary artery seen with conventional stenting.This prospective, multicenter, single-arm first-in-human study enrolled 50 patients in Belgium and Italy who were treated with the DynamX Bioadaptor. Eligible patients had de novo lesions in coronary arteries measuring between 2.5 and 3.5 mm in diameter and ≤ 24 mm in length. Clinical follow-up was performed up to 36 months. This analysis includes the intention-to-treat population and is based on data available. The preclinical studies include optical coherence tomography (OCT) analyses of 5 DynamX Bioadaptors implanted in 3 mini Yucatan pigs (at 3, 12 and 24 months), and assessment of smooth muscle cell gene expression profile in 8 pigs of which each was implanted with the DynamX Bioadaptor and the Xience drug-eluting stent. To assess the gene expression profile by quantitative real-time polymerase chain reaction, animals were sacrificed at 3, 6, 9 and 12 months.MethodsThis prospective, multicenter, single-arm first-in-human study enrolled 50 patients in Belgium and Italy who were treated with the DynamX Bioadaptor. Eligible patients had de novo lesions in coronary arteries measuring between 2.5 and 3.5 mm in diameter and ≤ 24 mm in length. Clinical follow-up was performed up to 36 months. This analysis includes the intention-to-treat population and is based on data available. The preclinical studies include optical coherence tomography (OCT) analyses of 5 DynamX Bioadaptors implanted in 3 mini Yucatan pigs (at 3, 12 and 24 months), and assessment of smooth muscle cell gene expression profile in 8 pigs of which each was implanted with the DynamX Bioadaptor and the Xience drug-eluting stent. To assess the gene expression profile by quantitative real-time polymerase chain reaction, animals were sacrificed at 3, 6, 9 and 12 months.Target lesion failure at 36 months was 8.7% (4/46), consisting of one clinically-driven target lesion revascularization and 3 cardiac deaths (all site-reported to be unrelated to the device or procedure). There were no additional target vessel revascularization and no definite or probable scaffold thrombosis. Preclinical data confirmed late lumen enlargement (from 7.02 ± 1.31 mm 2 at baseline to 8.46 ± 1.31 mm 2 at 24 months) and identified an increased expression of contractile genes around 9 months compared to a conventional drug-eluting stent.ResultsTarget lesion failure at 36 months was 8.7% (4/46), consisting of one clinically-driven target lesion revascularization and 3 cardiac deaths (all site-reported to be unrelated to the device or procedure). There were no additional target vessel revascularization and no definite or probable scaffold thrombosis. Preclinical data confirmed late lumen enlargement (from 7.02 ± 1.31 mm 2 at baseline to 8.46 ± 1.31 mm 2 at 24 months) and identified an increased expression of contractile genes around 9 months compared to a conventional drug-eluting stent.The DynamX Bioadaptor demonstrated very good 36-month clinical outcomes, highlighted by the absence of target-vessel myocardial infarction and definite or probable device thrombosis, and only one target lesion revascularization up to 36 months. These data are supported by preclinical studies that showed late lumen enlargement by OCT and an increased expression of contractile genes around 9 months compared to conventional drug-eluting stents, indicating faster vessel healing. Larger clinical studies are necessary to compare outcomes against contemporary drug-eluting stents.ConclusionsThe DynamX Bioadaptor demonstrated very good 36-month clinical outcomes, highlighted by the absence of target-vessel myocardial infarction and definite or probable device thrombosis, and only one target lesion revascularization up to 36 months. These data are supported by preclinical studies that showed late lumen enlargement by OCT and an increased expression of contractile genes around 9 months compared to conventional drug-eluting stents, indicating faster vessel healing. Larger clinical studies are necessary to compare outcomes against contemporary drug-eluting stents.https://clinicaltrials.gov/: NCT03429894.Clinical Trial Registrationhttps://clinicaltrials.gov/: NCT03429894.
Background
Contemporary data on left ventricular function (LVF) recovery in patients with left ventricular dysfunction after ST-elevation myocardial infarction (STEMI) are scarce and to date, no ...comparison has been made with patients with a baseline normal LVF. This study examined predictors of LVF recovery and its relation to outcomes in STEMI.
Methods
Patients presenting with STEMI between January 2010 and December 2016 were categorized in three groups after 3 months according to left ventricular ejection fraction (EF): (i) baseline normal LVF (EF ≥ 50% at baseline); (ii) recovered LVF (EF < 50% at baseline and ≥ 50% after 3 months); and (iii) reduced LVF (EF < 50% at baseline and after 3 months). Heart failure hospitalization, all-cause mortality and cardiovascular mortality were compared between the three groups.
Results
Of 577 patients, 341 (59%) patients had a baseline normal LVF, 112 (19%) had a recovered LVF and 124 (22%) had a reduced LVF. Independent correlates of LVF recovery were higher baseline EF, lower peak troponin and cardiac arrest. After median 5.8 years, there was no difference in outcomes between patients with LVF recovery and baseline normal LVF. In contrast, even after multivariate adjustment, patients with persistently reduced LVF had a higher risk for heart failure hospitalization (HR 5.00; 95% CI 2.17–11.46) and all-cause mortality (HR 1.87; 95% CI 1.11–3.16).
Conclusion
In contemporary treated STEMI patients, prognosis is significantly worse in those with a persistently reduced LVF after 3 months, compared with patients with a baseline normal LVF and those with LVF recovery.
Graphic abstract
To report the six-month angiographic and two-year clinical outcome data from the first-in-man study with the Ultimaster DES, a thin-strut cobalt-chromium sirolimus-eluting stent (SES) with an ...innovative abluminal-gradient-coated bioresorbable polymer.
CENTURY is a multicentre, single-arm, prospective study that enrolled 105 patients (113 lesions) with coronary artery disease. All patients were scheduled to have an angiographic follow-up at six months, while 45 and 20 patients respectively had IVUS and OCT assessments. The primary endpoint was six-month in-stent late lumen loss. Secondary endpoints included clinical, IVUS and OCT outcomes. Clinical follow-up is available up to two years and will continue up to five years. Procedural success was 97.1% and device success was 100%. Angiographic late loss at six months was 0.04±0.35 mm, also reflected in a low binary restenosis rate of 0.9% and confirmed by IVUS-assessed neointimal volume obstruction of 1.02±1.62%. The mean strut coverage assessed by OCT was 96.2% with 1.66±4.02 malapposed stent struts. There were no deaths in the study, three (2.9%) periprocedural and one (0.9%) spontaneous myocardial infarction, not related to the target vessel. At one and two years, the target lesion failure rate was 3.8% and 5.7%, while the TLR rate was 1.9% and 2.8%, respectively. There was one acute definite stent thrombosis.
The Ultimaster™ novel bioresorbable polymer sirolimus-eluting stent demonstrated good performance, including high procedural success and strong suppression of neointimal proliferation at six months. Good safety and effectiveness were shown up to two years in the studied population.
The aim of this study was the external validation of the updated logistic clinical SYNTAX score for two-year all-cause mortality after PCI in the GLOBAL LEADERS trial.
The GLOBAL LEADERS trial was an ...investigator-initiated, prospective randomised, multicentre, open-label trial comparing two strategies of antiplatelet therapy in 15,991 patients undergoing PCI. As a predefined analysis, we studied the first 4,006 consecutive patients enrolled between July 2013 and April 2014 for whom the anatomic SYNTAX scores were calculated by an independent core lab. The updated logistic clinical SYNTAX score was available in 3,271 patients. Patients were divided into quintiles according to the score. The C-statistic of the updated logistic clinical SYNTAX score for two-year all-cause mortality was 0.71 (95% confidence interval CI: 0.64-0.77). The updated logistic clinical SYNTAX score identified patients at very high risk for two-year all-cause mortality after PCI. Although it systematically overestimated two-year all-cause mortality, predicted and observed two-year all-cause mortality in the majority of the patients (four out of five quintiles) were in agreement.
Overall discrimination for two-year all-cause mortality of the updated logistic clinical SYNTAX score is either borderline acceptable or possibly helpful. Calibration in the majority of patients is appropriate. The score is potentially useful in selecting enriched high-risk populations.
Quantitative flow ratio (QFR) based on three-dimensional quantitative coronary angiography (3D-QCA) is a novel method to assess physiological functionality after treatment with stents. The current ...study aimed to evaluate the difference in physiological functionality nine months after implantation of a bioresorbable polymer-based sirolimus-eluting stent with an electrografting base layer (BuMA Supreme: B-SES) versus a durable polymer-based zotarolimus-eluting stent (Resolute: R-ZES).
The current post hoc analysis was performed in the PIONEER randomised trial (1:1 randomisation to B-SES 83 patients/95 lesions and R-ZES 87 patients/101 lesions). QFR was measured in stented vessels in both arms at preprocedural, post-procedural and nine-month angiography without pharmacologically induced hyperaemia (contrast QFR). At nine months, both the values of QFR distal to the stent (B-SES: 0.89±0.10 vs. R-ZES: 0.89±0.11, p=0.97) and the number of vessels with QFR ≤0.8 were not significantly different between the two groups (11.0% vs. 12.8%, p=0.72), while the in-stent binary restenosis rate was also comparable (3.7% vs. 3.5%, p=1.00). QFR gradient across the device (∆QFR) at nine months was also similar between the groups (B-SES: 0.03±0.04 vs. R-ZES: 0.03±0.07, p=0.95).
Quantitative flow assessment nine months after stenting did not differ between B-SES and R-ZES, despite a significant difference in in-stent late lumen loss.
Objective
Recruitment and retention in trials may bias the results and subsequently complicate their interpretation and validity. The aim of this study is to evaluate the impact of recruitment and ...retention on all-cause mortality in a large all-comers trial.
Methods
The recruitment rate in each investigating center of the GLOBAL LEADERS trial was assessed and the 130 centers were subdivided into low and high recruiters according to the median, with all-cause mortality then compared between the two groups. Vital status was obtained from public records in patients with incomplete follow-up.
Results
The trial randomized 15,991 (7.86%) of 203,483 eligible patients with percutaneous coronary intervention during the recruitment period, of whom 15,267 (95.47%) completed follow-up, 23 (0.14%) patients withdrew consent and formally requested to be deleted from the database; 183 (1.14%) withdrew consent but only objected to future data collection; 303 (1.89%) discontinued the study; and 215 (1.34%) were lost to follow-up. Vital status was finally obtained in all but 31 patients (99.81%). Patients from low recruiters had a significantly lower all-cause mortality than high ones (2.26% vs. 3.24%; hazard ratio: 0.69; 95% confidence interval: 0.55–0.87;
p
= 0.002). There was a significant difference in all-cause mortality among the incomplete follow-up groups (log-rank
p
< 0.001) with a significantly higher mortality in the 183 patients who withdrew consent than those who completed follow-up (7.38% vs. 2.99%,
p
= 0.002).
Conclusions
Recruitment and retention significantly impacted all-cause mortality. Search for vital status through public domains is of paramount importance in the interpretation and validity of large clinical trials.
Graphic abstract
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