Abstract: We included 38 randomised controlled trials involving 1907 participants (1114 cell therapy, 793 controls) in this review update. Twenty-three trials were at high or unclear risk of selection bias. Other sources of potential bias included lack of blinding of participants (12 trials) and full or partial commercial sponsorship (13 trials). Cell therapy reduced the incidence of long-term mortality (≥ 12 months) (risk ratio (RR) 0.42, 95% confidence interval (CI) 0.21 to 0.87; participants = 491; studies = 9; I2 = 0%; low-quality evidence). Periprocedural adverse events associated with the mapping or cell/placebo injection procedure were infrequent. Cell therapy was also associated with a long-term reduction in the incidence of non-fatal myocardial infarction (RR 0.38, 95% CI 0.15 to 0.97; participants = 345; studies = 5; I2 = 0%; low-quality evidence) and incidence of arrhythmias (RR 0.42, 95% CI 0.18 to 0.99; participants = 82; studies = 1; low-quality evidence). However, we found no evidence that cell therapy affects the risk of rehospitalisation for heart failure (RR 0.63, 95% CI 0.36 to 1.09; participants = 375; studies = 6; I2 = 0%; low-quality evidence) or composite incidence of mortality, non-fatal myocardial infarction, and/or rehospitalisation for heart failure (RR 0.64, 95% CI 0.38 to 1.08; participants = 141; studies = 3; I2 = 0%; low-quality evidence), or long-term left ventricular ejection fraction when measured by magnetic resonance imaging (mean difference -1.60, 95% CI -8.70 to 5.50; participants = 25; studies = 1; low-quality evidence). This systematic review and meta-analysis found low-quality evidence that treatment with bone marrow-derived stem/progenitor cells reduces mortality and improves left ventricular ejection fraction over short- and long-term follow-up and may reduce the incidence of non-fatal myocardial infarction and improve New York Heart Association (NYHA) Functional Classification in people with chronic ischaemic heart disease and congestive heart failure. These findings should be interpreted with caution, as event rates were generally low, leading to a lack of precision.

Plain-language summary: We included 38 randomised controlled trials involving more than 1900 participants in this review, with 14 trials of chronic ischaemic heart disease, 17 trials of ischaemic heart failure secondary to heart disease, and seven trials of refractory or intractable angina. The mean age of participants ranged from 55 to 70 years, and the proportion of male participants ranged from 51% to 100%. Results indicated that treatment with bone marrow-derived cells can lead to a reduction in deaths in participants followed for at least 12 months. Adverse events occurring around the time of treatment were generally rare. Participants who received cell treatment also experienced fewer heart attacks and arrhythmias when compared to those who received no cells. However, cell therapy does not appear to reduce the risk of rehospitalisation for heart failure or the combined risk of death, non-fatal heart attack, or rehospitalisation, and did not result in any improvement over standard treatment in tests of heart function. These results suggest that cell therapy may be of benefit in people with chronic ischaemic heart disease or heart failure, or both. The quality of the evidence was low, as the number of included studies and participants is not currently high enough to draw robust conclusions. Thirteen studies received commercial funding, of which four were fully commercially sponsored, and 12 studies did not report that participants were blinded to the treatment they received. Further research involving a larger number of participants is required to confirm our results.