Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

Florea, Victoria; Rieger, Angela C.; DiFede, Darcy L.; El-Khorazaty, Jill; Natsumeda, Makoto; Banerjee, Monisha N.; Tompkins, Bryon A.; Khan, Aisha; Schulman, Ivonne Hernandez; Landin, Ana Marie; Mushtaq, Muzammil; Golpanian, Samuel; Lowery, Maureen H.; Byrnes, John; Hendel, Robert C.; Cohen, Mauricio G.; Valasaki, Krystalenia; Pujol, Marietsy V.; Ghersin, Eduard; Miki, Roberto A.; Delgado, Cindy; Abuzeid, Fouad; Vidro-Casiano, Mayra; Saltzman, Russell G.; DaFonseca, Daniel; Caceres, Lina V.; Ramdas, Kevin; Mendizabal, Adam; Heldman, Alan W.; Mitrani, Raul D.; Hare, Joshua M.

doi:10.1161/circresaha.117.311827

Cited by 159 publications

(135 citation statements)

References 32 publications

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“…Interestingly, this study provides evidence against that paradigm because both groups experienced improvements in quality of life, highlighting the importance of evaluating a variety of efficacy end points rather than a single functional parameter to determine the overall benefit from cell‐based therapies, an idea supported by several investigators in the field 27, 28, 29, 30. Similarly, several clinical trials evaluating cell‐based therapies for both forms of HF found that stem cells improved quality of life and functional parameters without sustained improvements in EF 31, 32, 33, 34. Although both patient populations experienced quality‐of‐life improvements, the MLHFQ score improved more in the DCM group.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Tompkins

Rieger²,

Florea³

et al. 2018

JAHA

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BackgroundIschemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done.Methods and ResultsWe conducted a subanalysis of 3 single‐center, randomized, and blinded clinical trials: (1) TAC‐HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON‐DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1‐year cardiac structure and function and quality‐of‐life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within‐group, P=0.002) compared to ICM (1.5%; within‐group, P=0.14; between‐group, P=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (P=0.046) versus ICM (−0.2 mL; P=0.73; between‐group, P=0.02). End‐diastolic volume improved only in ICM (10.6 mL; P=0.04) and end‐systolic volume improved only in DCM (17.8 mL; P=0.049). The sphericity index decreased only in ICM (−0.04; P=0.0002). End‐diastolic mass increased in ICM (23.1 g; P<0.0001) versus DCM (−4.1 g; P=0.34; between‐group, P=0.007). The 6‐minute walk test improved in DCM (31.1 m; P=0.009) and ICM (36.3 m; P=0.006) with no between‐group difference (P=0.79). The New York Heart Association class improved in DCM (P=0.005) and ICM (P=0.02; between‐group P=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (−19.5; P=0.002) and ICM (−6.4; P=0.03; δ between‐group difference P=0.042) patients.ConclusionsMesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: TAC‐HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON‐DCM: NCT01392625.

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Section: Discussionmentioning

confidence: 99%

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Tompkins

Rieger²,

Florea³

et al. 2018

JAHA

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“…Cell‐based therapy has been studied in ischemic and nonischemic cardiomyopathies and has been shown to be associated with modest improvement in heart function and no pro‐arrhythmia . A subanalysis of the POSEIDON trial demonstrated that patients with large ischemic scars had greater improvement in contractility with significant decrease in the scar size in injected scar segments with transendocardial mesenchymal stem cell (MSC) when compared to noninjected segments .…”

Section: Introductionmentioning

confidence: 99%

A meta‐analysis of arrhythmia endpoints in randomized controlled trials of transendocardial stem cell injections for chronic ischemic heart disease

Fernandes

Rivera

et al. 2019

Cardiovasc electrophysiol

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Introduction The electrophysiologic impact of cell‐based therapy on the injured myocardium remains highly controversial. We aimed to perform a meta‐analysis of studies comparing arrhythmia burden following transendocardial stem cell therapy vs placebo in patients with chronic ischemic heart disease (CIHD). Methods and Results PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. No restriction of stem cell type was specified. The outcomes included sustained supraventricular or ventricular arrhythmias (VAs), sudden cardiac death (SCD), and resuscitated sudden cardiac arrest (SCA). Effect sizes were reported as odds ratio (OR) and 95% CI. Poisson regression was used to account for zero‐events data. Twelve randomized trials that included 736 patients (384 in the cell therapy group and 352 in the placebo group) were analyzed. Six different cell types were used. Follow‐up ranged from 6 to 12 months. There was a significant decrease in risk of SCD in the cell therapy group, (FE OR, 0.19 [0.04, 0.93]; P = .04). In subgroup analysis, there was a significantly lower risk of SCD or resuscitated SCA in the cell therapy group limited to studies that did not use skeletal myoblasts, (FE OR, 0.23 [0.06, 0.83]; P = .03). There was no significant difference in the incidence of sustained VA between groups (FE OR, 0.91 [0.47, 1.77]; P = .8), even after stratifying by cell type. There was no difference in supraventricular arrhythmias between groups. Conclusion Nonskeletal myoblast transendocardial cell therapy was associated with a significantly lower risk of SCD or resuscitated SCA compared to control, with no proarrhythmic effects.

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“…Toward addressing this knowledge gap, the TRIDENT Study – presented in this issue of Circulation Research – compared outcomes following randomized treatment with two doses of allogeneic bone marrow-derived human mesenchymal stem cells (hMSC) in patients with chronic ischemic cardiomyopathy. 8 Thirty patients received either 20 or 100 million cells identically delivered, in a blinded manner, via transendocardial injection (ten 0.5 cc injections/patient). At one year follow-up, both cell doses were safe and well tolerated with favorable impact on reducing post-infarction scar size, but only the larger dose was associated with improved ejection fraction.…”

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“…In the context of the TRIDENT trial, the higher dose may provide greater benefit than the lower dose suggesting a direct relationship between cell dose and clinical efficacy at least within the dose range tested, a conclusion supported by pro-BNP levels which remained stable only in the 100 million hMSC-treated group. 8 The TRIDENT study therefore adds to an increasing compendium of clinical experience for use of cell-based technology in patients with heart disease. As recognized by the TRIDENT investigators, the study was limited by lack of a placebo group and small sample size testing two distinct doses.…”

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“…It has been suggested that intracoronary injections, typically used in treating acute conditions, require cells to extravasate and migrate to the areas of injury which may result in lower engraftment rates than intramyocardial injections, thus requiring higher initial doses. 8 Moreover, in the context of severe hypoxia and inflammation germane to acute myocardial infarction, the recently injured tissue is unlikely to mimic a chronic disease state and as such may dictate distinct doses and treatment schedules.…”

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Posology for Regenerative Therapy

Terzic

Behfar

2017

Circulation Research

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Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

Cited by 159 publications

References 32 publications

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

A meta‐analysis of arrhythmia endpoints in randomized controlled trials of transendocardial stem cell injections for chronic ischemic heart disease

Posology for Regenerative Therapy

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