Target-specific cardiotoxicity of tyrosine kinase inhibitors: a Systematic Review and meta-analysis

FIGURE 1. PRISMA 2020 flow diagram of the study selection process. The flow diagram summarizes the study selection process according to the PRISMA 2020 guidelines. The numbers of records identified through database searching, duplicates removed, records screened, full-text articles assessed for eligibility, and studies ultimately included are shown. Reasons for exclusion at the full-text stage are provided.

FIGURE 2. Forest plot of MACEs comparing tyrosine kinase inhibitors (TKIs) with placebo in patients with advanced malignancies. For MACEs, a fixed-effects model was used (I2 = 0%, P = 0.98). Squares represent the effect estimate (odds ratio [OR]) for each individual study; the size of each square is proportional to the weight assigned to that study in the meta-analysis. Horizontal lines indicate the 95% confidence interval (CI) for each study. The diamond at the bottom of the forest plot represents the pooled effect estimate; the width of the diamond corresponds to the 95% CI of the pooled estimate. Abbreviations: TKI, tyrosine kinase inhibitor; CI, confidence interval; OR, odds ratio; MACEs, major adverse cardiovascular events.

FIGURE 3. Subgroup analysis of MACE risk by TKI target class (EGFR-TKIs, VEGFR-TKIs, PDGFR-TKIs) compared with placebo. For subgroup analysis, a fixed-effects model was used (EGFR: I2 = 0%, P = 0.05; VEGFR: I2 = 0%, P = 0.65; PDGFR: I2 = 0%, P = 0.65). Squares represent the effect estimate (OR) for each individual study; the size of each square is proportional to the weight assigned to that study in the meta-analysis. Horizontal lines indicate the 95% CI for each study. The diamond at the bottom of each forest plot represents the pooled effect estimate; the width of the diamond corresponds to the 95% CI of the pooled estimate. Abbreviations: TKI, tyrosine kinase inhibitor; EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; CI, confidence interval; OR, odds ratio; MACEs, major adverse cardiovascular events.

FIGURE 4. Subgroup analysis of MACE risk comparing single-target TKIs and multi-target TKIs, with placebo as the common reference. For subgroup analysis, a fixed-effects model was used (single-target TKIs: I2 = 0%, P = 0.05; multi-target TKIs: I2 = 0%, P = 0.65). Squares represent the effect estimate (OR) for each individual study; the size of each square is proportional to the weight assigned to that study in the meta-analysis. Horizontal lines indicate the 95% CI for each study. The diamond at the bottom of each forest plot represents the pooled effect estimate; the width of the diamond corresponds to the 95% CI of the pooled estimate. Abbreviations: TKI, tyrosine kinase inhibitor; CI, confidence interval; OR, odds ratio; MACEs, major adverse cardiovascular events.

FIGURE 5. Forest plots of CVAEs associated with TKIs compared with placebo: (A) arrhythmias, (B) QT interval prolongation, and (C) hypertension. For arrhythmias, a fixed-effects model was used (I2 = 5%, P < 0.00001). For QT interval prolongation, a random-effects model was used (I2 = 38%, P < 0.00001). For hypertension, a random-effects model was used (I2 = 90%, P < 0.0001). Squares represent the effect estimate (OR) for each individual study; the size of each square is proportional to the weight assigned to that study in the meta-analysis. Horizontal lines indicate the 95% CI for each study. The diamond at the bottom of each forest plot represents the pooled effect estimate; the width of the diamond corresponds to the 95% CI of the pooled estimate. Abbreviations: TKI, tyrosine kinase inhibitor; CI, confidence interval; OR, odds ratio; CVAEs, cardiovascular adverse events.