Key result
Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR 2.11), and their combination with chemotherapy increased the risk of all-grade (OR 1.53) and grade 3-5 cardiotoxicity (OR 1.63) compared with chemotherapy alone.
Why the study?
PD-1/PD-L1 inhibitors have improved cancer outcomes but increased adverse events, warranting a systematic evaluation of cardiovascular toxicity risk.
Do PD-1/PD-L1 inhibitors increase the risk of cardiovascular toxicity in cancer patients?
Systematic Review (n=33,166)
Do PD-1/PD-L1 inhibitors increase the risk of cardiovascular toxicity in cancer patients?
Odds Ratio: 2.11 (95% CI 1.02–4.36)
p-value: p=0.04
PD-1/PD-L1 inhibitors, particularly when combined with chemotherapy, significantly increase the risk of cardiovascular toxicity, including arrhythmias and hypertension, in cancer patients.
Warrants cardiovascular monitoring with PD-1/PD-L1 inhibitors; confirms elevated all-grade cardiotoxicity risk versus placebo in RCT meta-analysis.
Background PD-1/PD-L1 inhibitors have significantly improved the outcomes of those patients with various malignancies. However, the incidence of adverse events also increased. This meta-analysis aims to systematically evaluate the risk of cardiovascular toxicity in patients treated with PD-1/PD-L1 inhibitors. Materials and methods We searched PubMed, Embase, the Cochrane Library databases for all randomized controlled trials (RCTs) comparing all-grade and grade 3-5 cardiovascular toxicity of single-agent PD-1/PD-L1 inhibitors to placebo/chemotherapy, PD-1/PD-L1 inhibitors combined with chemotherapy to chemotherapy, or PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors to single-agent immune checkpoint inhibitors (ICIs) and pooled our data in a meta-analysis stratified by tumor types and PD-1 or PD-L1 inhibitors. The Mantel-Haenszel method calculated the odds ratio (OR) and its corresponding 95% confidence intervals (CIs). Results A total of 50 trials were included in the analysis. Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR=2.11, 95%CI 1.02-4.36, P= 0.04). Compared with chemotherapy, patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a significant higher risk of all-grade (OR=1.53, 95%CI 1.18-1.99, P= 0.001) and grade 3-5 cardiotoxicity (OR=1.63, 95%CI 1.11-2.39, P= 0.01) cardiotoxicity, especially patients with non-small cell lung cancer (NSCLC) [all-grade cardiotoxicity (OR=1.97, 95%CI 1.14-3.41, P= 0.02) and grade 3-5 cardiotoxicity (OR=2.15, 95%CI 1.08-4.27, P= 0.03)]. Subgroup analysis showed that PD-1 inhibitors combined with chemotherapy were associated with a higher risk of grade 3-5 cardiotoxicity (OR=2.08, 95%CI 1.18-3.66, P= 0.01). Compared with placebo or chemotherapy, single-agent PD-1/PD-L1 inhibitors did not increase the risk of all-grade of myocarditis, arrhythmia and hypertension. However, PD-1/PD-L1 inhibitors combined with chemotherapy increased the risk of all-grade arrhythmia (OR=1.63, 95%CI 1.07-2.46, P= 0.02) [PD-L1 inhibitor-containing treatment (OR=1.75, 95%CI 1.09-2.80, P= 0.02)], and the risk of all-grade hypertension (OR=1.34, 95%CI 1.02-1.77, P= 0.04) and grade 3-5 hypertension (OR=1.54, 95%CI 1.10-2.15, P= 0.01). Conclusions Our results suggest that single-agent PD-1/PD-L1 inhibitors increase the risk of all-grade cardiotoxicity, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of all-grade and grade 3-5 cardiotoxicity, especially in those patients treated with PD-1 inhibitor-containing treatment and those with NSCLC. In addition, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of arrhythmia and hypertension. Therefore, this evidence should be considered when assessing the benefits and risks of PD-1/PD-L1 inhibitors in treating malignancies. Systematic Review Registration https://www.crd.york.ac.uk/prospero/ , identifier CRD42022303115.
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Liu et al. (2022) conducted a systematic review in Cancer (n=33,166). PD-1/PD-L1 inhibitors vs. Placebo or chemotherapy was evaluated on All-grade cardiotoxicity (single-agent vs placebo) (OR 2.11, 95% CI 1.02-4.36, p=0.04). Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR 2.11), and their combination with chemotherapy increased the risk of all-grade (OR 1.53) and grade 3-5 cardiotoxicity (OR 1.63) compared with chemotherapy alone.
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