Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis

Abstract

Aims The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown. Methods and results We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56–12.50, P < 0.01; I2 = 0%, P = 0.93) and dyslipidemia (Peto OR: 3.68, 95% CI: 1.89–7.19, P < 0.01; I2 = 0%, P = 0.66). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0–5.1) to 19.3 (6.7–54.1) per 1000 patients, in studies with a median follow-up ranging from 3.2 to 32.8 months. Conclusion In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis.

Immunotherapeutic Strategies in Cancer and Atherosclerosis—Two Sides of the Same Coin

“…In a meta-analysis of 112 trials including 19,217 patients, IRAE-associated fatality rates ranged between 0.36% for anti-PD-1 mono-therapy and 1.23% for PD1/PD-L1 plus CTLA-4 combinational therapy and were most commonly caused by colitis, pneumonitis, hepatitis, myocarditis and neurotoxic effects ( 145 ). Cardiovascular IRAEs, which include myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischemia, are, overall, relatively rare with an incidence ranging between ~3 and 20 per 1,000 patients ( 146 ). Yet, cardiovascular toxicities are severe in over 80% of cases ( 147 ) and myocarditis, which carries the highest fatality risk of all IRAEs (40–50%), is of particular prognostic relevance ( 145 , 147 ).…”

Cardiovascular disease and malignant melanoma

“…Administration of PD-1 antibodies in these mice further increased lesional inflammation and T-cell recruitment [64]. The converse is also true; stimulation of PD-1 pathways protect against atherosclerosis by modulating T-cell activityreducing interferon-gamma producing CD4+ T cells and increasing atheroprotective Real world: 0.3-1.9% [5,55,71] Trials: 0.8% [7] a From studies with minimum of 12 months average/median follow-up.…”

“…From observational studies and meta-analyses of trials, ICI therapy has been associated with an increased risk of heart failure [5,7,52]. Although the association remains unclear as studies do not have clear definitions of heart failure making it not possible to discern between worsening of preexisting chronic heart failure, development of de-novo heart failure/cardiomyopathy or undiagnosed ICI-associated myocarditis.…”

“…In addition to melanoma recurrence and the development of other cutaneous malignancies, patients may be at an increased risk of cardiovascular diseases. Recent studies show an increased risk of myocardial infarction, myocarditis, heart failure, pericardial and cerebrovascular disease in patients treated with ICI [4][5][6][7]. Cardiovascular disease is increasingly relevant in cancer survivors; as cardiovascular mortality surpasses cancer-specific mortality for some high-survival cancers [8,9].…”

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety

“…In a recent pharmacovigilance analysis, it was found that cardiac irAEs in the vigiAccess database were mainly associated with myocarditis ( Rubio‐Infante et al, 2021 ). Recently in a metanalysis of randomized clinical trials including 32,518 patients, the ICIs therapies were associated with an increased risk of six different cardiac irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischemia with a higher risk for myocarditis development (Peto OR: 4.42, 95% CI: 1.56–12.50, p < 0.01) ( Dolladille et al, 2021 ). Despite, in a study by Agostinetto et al , neither significant differences were found in cardiac irAEs between ICI and non-ICI groups (RR 1.14, 95% CI 0.88–1.48, p = 0.326), nor between dual ICI and single ICI groups ( Agostinetto et al, 2021 ).…”