Risk of Major Adverse Cardiovascular Events in Patients With Inflammatory Bowel Diseases or Other Immune-Mediated Inflammatory Disorders on Biologics and Small Molecules: A Systematic Review and Network Meta-Analysis

Introduction: Recent studies raise concern for an increased risk of major adverse cardiovascular events (MACE) with Janus Kinase inhibitors (JAKi) used to treat immune-mediated inflammatory disorders (IMIDs). Our aim was to examine MACE risk with all licensed biologics and small molecules for patients with inflammatory bowel disease and other IMIDs such as psoriasis/Psoriatic arthritis and rheumatoid arthritis. Methods: Data were obtained from systematic searches (from 1989 to May 31, 2022) in PubMed, Embase, Ovid Medline, Scopus, Cochrane Central, and Clinicaltrials.gov. Comparative studies that assessed a pre-defined MACE risk in patients with IMIDs during treatment with anti-interleukin-23 antibodies (anti-IL-23), anti-interleukin 12/23 antibodies (anti-IL-12/23), anti-tumor necrosis factor-alpha antibodies (anti-TNF-α) or JAKi were included. We performed a network meta-analysis using a random-effects model with results as pooled odds ratios (ORs) with 95% credible intervals (CrIs) according to drug class and disease state. Results: Among 3,528 studies identified, 40 (including 36 randomized controlled trials [RCTs] and 4 cohort studies) were included in the systematic review, comprising 126,961 patients with IMIDs (Figure 1). Based on the network meta-analysis of RCTs, regardless of disease state, anti-TNF-α (OR, 2.49; 95% CrI: 1.14-5.62), JAKi (OR, 2.64; 95% CrI: 1.26-5.99), and anti-IL-12/23 (OR, 3.15; 95% CrI: 1.01-13.35) were associated with increased risk of MACE when compared to placebo, while anti-IL-23 (OR, 2.65; 95% CrI: 0.85-10.03) was not associated with an increased risk of MACE (Table 1). The magnitude of the increased risk of MACE with different drug classes was not significantly different when compared by IMID type. Conclusion: In this meta-analysis, we found that JAKi, anti-TNF-α, and anti-IL-12/23 increased the risk of MACE, while anti-IL-23 did not. We did not find a differential risk of MACE when stratified by disease state. Larger prospective studies are needed to confirm these findings.Figure 1.: Network plot for occurrence of major adverse cardiovascular events according to drug class. Each node (circle) denotes a drug class. The node size is proportional to the total number of study patients assigned to each drug class. The line width (connection size) corresponds to the number of studies comparing the drug classes. Abbreviations: Abs, antibodies; IL, interleukin; JAK, Janus Kinase; TNF-α, tumor necrosis factor-alpha. Table 1. - League Table for Network Meta-Analysis of Occurrence of Major Adverse Cardiovascular Events According to Drug Class Anti-IL-12/23 antibodies 1.13 (0.25-6.44) Anti-IL-23 antibodies 1.29 (0.28-6.10) 1.03 (0.32-4.23) Janus Kinase inhibitors 1.31 (0.27-5.78) 1.04 (0.33-3.68) 1.02 (0.59-2.17) Anti-TNF-α antibodies 3.15 (1.01-13.35) 2.65 (0.85-10.03) 2.64 (1.26-5.99) 2.49 (1.14-5.62) Placebo Note: Drug classes are ranked according to their SUCRA: anti-TNF-α antibodies, 0.57; Janus Kinase inhibitors, 0.59; anti-IL-23 antibodies, 0.60; anti-IL-12/23 antibodies, 0.70. The estimates are reported as odds ratios with 95% credible intervals (in parentheses). The comparison between the drug classes should be read from left to right by comparing columns with rows. Abbreviations: SUCRA, surface under the cumulative ranking curve; IL, interleukin; TNF-α, tumor necrosis factor-alpha.