Severe cardiac events induced by combination immunotherapy in patients with cancer: a meta-analysis.

Introduction: The use of combined immunotherapy could increase non-severe and severe cardiac events in patients with cancer. To examine the occurrence of severe cardiac adverse events of combined immunotherapy compared to single immunotherapy, we analysed 4 electronic databases from inception to August 2021. Material and methods: We selected randomized controlled trials (RCTs) comparing combined versus single immunotherapy, for the treatment of melanoma, oesophagogastric cancer, renal cell carcinoma, and non-small cell lung cancer. Pre-defined combined immunotherapy included monoclonal antibodies against programmed cell death 1 (PD-1 inhibitors) plus against cytotoxic T lymphocyte antigen 4 (CTLA-4 inhibitors) or against programmed cell death ligand 1 (PD-L1 inhibitors) plus CTLA-4 inhibitors. The pooled risk ratios (RR) with their 95% confidence intervals (CI) were estimated using a random-effects model. Results: Four RCTs involving 1581 patients were included, with a follow-up time between 18 and 39 months. The use of combined immunotherapy in comparison with single immunotherapy was not associated with an increased risk of severe cardiac adverse events: acute coronary syndromes (RR = 1.76, 95% CI: 0.29-10.83, very low certainty of evidence (CoE)), myocardial infarction (RR = 3.93, 95% CI: 0.44-35.39, very low CoE), heart failure (RR = 2.99, 95% CI: 0.61-14.79, very low CoE), and atrial fibrillation (RR = 2.26, 95% CI: 0.62-8.16, very low CoE). Conclusions: Our meta-analysis shows that the risk of severe cardiac adverse events with combined immunotherapy seems similar to single immunotherapy, but the evidence is very uncertain. Therefore, more RCTs with longer follow-ups and adequately powered to assess cardiac adverse events are needed to confirm these findings.