The Impact of Cell Therapy on Cardiovascular Outcomes in Patients With Refractory Angina

Abstract

Rationale: Cell-based therapies are a novel potential treatment for refractory angina and have been found to improve markers of angina. However, the effects on mortality and major adverse cardiac events (MACE) have not been definitively investigated. Objective: To investigate the efficacy and safety of stem cell treatment compared with optimal medical treatment for refractory angina by conducting an updated meta-analysis, looking at clinical outcomes. Methods and Results: We performed a systematic review and meta-analysis of randomized controlled trials using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A comprehensive search was performed of PubMed, EMBASE (Excerpta Medica database), Cochrane, ClinicalTrials.gov , Google Scholar databases of randomized controlled trials, and scientific session abstracts. Studies were deemed eligible if they met the following criteria: (1) full-length publications in peer-reviewed journals; (2) evaluated cell therapy use in patients with no further revascularisation options while on optimal medical treatment; (3) patients had ongoing angina, Canadian Cardiovascular Society class II—IV; and (4) included a placebo/control arm. We calculated risk ratios for all-cause mortality, combined MACE events. We assessed heterogeneity using χ 2 and I 2 tests. We identified 1191 citations with 8 randomized controlled trials meeting inclusion criteria involving 526 patients. Outcomes pooled were MACE, mortality, and indices of angina (angina episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications). Our analysis showed a decreased risk of both MACE (odds ratio, 0.41; CI, 0.25−0.70) and mortality (odds ratio, 0.24; 95% CI, 0.10−0.60) in cell-treated patients compared with patients on maximal medical therapy. This was supported by improvements in surrogate end points of anginal episodes, use of antianginal medications, Canadian Cardiovascular Society class, and exercise tolerance. Conclusions: In addition to improvements in indices of angina, cell-based therapies improve cardiovascular outcomes (mortality/MACE) in patients with refractory angina. Given the premature termination of the phase III study, this supports the need for further definitive trials. Prospero Registration : URL: https://www.crd.york.ac.uk/prospero/ . Unique identifier: CRD42018084257.

Son of a Lesser God: The Case of Cell Therapy for Refractory Angina

“…As for safety, the risk of MI and stroke did not differ in patients treated with CD34 + cells with respect to placebo (odd ratio (OR) [95%CI]: 0.77 [0.36, 1.63] and 0.50 [0.08, 3.06], respectively), but, in return, the overall risk of mortality was significantly lower in CD34 + cell than in placebo group (0.24 [0.08, 0.73], p = 0.01) ( 117 ). Finally, the most updated systematic review further confirmed that CT in RA patients entails lower incidence of MACE (OR [95%CI]: 0.41 [0.25, 0.70], p < 0.0001) and all-cause mortality (0.24 [0.10, 0.60], p = 0.002) respect to placebo/controls ( 116 ). Interestingly, the subgroup analysis revealed that the favorable outcome in the pooled analysis is primarily driven by data derived from clinical studies with CD34 + cells which embody the largest patient cohort (74%) ( 116 ).…”

“…Finally, the most updated systematic review further confirmed that CT in RA patients entails lower incidence of MACE (OR [95%CI]: 0.41 [0.25, 0.70], p < 0.0001) and all-cause mortality (0.24 [0.10, 0.60], p = 0.002) respect to placebo/controls ( 116 ). Interestingly, the subgroup analysis revealed that the favorable outcome in the pooled analysis is primarily driven by data derived from clinical studies with CD34 + cells which embody the largest patient cohort (74%) ( 116 ). Recently, the retrospective analysis of phase I/IIa, phase II ACT-34 and phase III RENEW was published showing that RA patients who received CD34 + cell therapy experienced the reduction of hospitalizations, cardiac procedures, and health care expenditures in the first year following treatment compared to the year prior ( 121 ).…”

“…To combine multiple clinical research results, six MTA were conducted so far and the cumulative results on CT safety and efficacy have been shown (115)(116)(117)(118)(119)(120) The risk of all-cause mortality was similar in patients treated with CT or placebo (p = 0.121). It is important to point out that such results, although promising, derived from the pooled effect of different cell products and, thus, cannot be deemed conclusive but only hypothesis-generating.…”

“…Non-pharmacological treatment options in the 2019 ESC and 2012-2014 ACC/AHA guidelines for refractory angina vs. cell therapy.CD34 + cells which embody the largest patient cohort (74%)(116). Recently, the retrospective analysis of phase I/IIa, phase II ACT-34 and phase III RENEW was published showing that RA patients who received CD34 + cell therapy experienced the reduction of hospitalizations, cardiac procedures, and health care expenditures in the first year following treatment compared to the year prior(121).…”

Non-pharmacological Treatment of Refractory Angina and Microvascular Angina

“…Moreover, improvements in myocardial perfusion were positively correlated with the proangiogenic growth factors, hepatocyte growth factor and platelet-derived growth factor type bb, substances involved in neovascularization, endothelial and muscle cell growth [85,86]. The most recent and the largest (8 RCTs, 526 patients) meta-analysis to date concluded that cell-based therapies improve not only indices of angina (angina episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications), but also mortality and major adverse cardiovascular events [87,88].…”