Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d415730e284">Background.</h5> <p id="P8">Immune-checkpoint-inhibitors (ICIs) have dramatically improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations. However, ICIs can also cause severe or even fatal immune-mediated adverse-events (irAE). Here, we identify and characterize significant cardiovascular irAE (CV-irAEs) associated with ICIs. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d415730e289">Methods.</h5> <p id="P9">We used VigiBase, the WHO’s global Individual-Case-Safety-Report database to identify drug-AE related to ICIs (n:31,321) and related to other drugs (n:16,343,451) through 01/2018. We evaluated the association between ICI and CV events using Reporting-Odds-Ratio (ROR) and Information-Component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find drug-AE associations. IC ₀₂₅ is the lower-end of IC 95% credibility-interval and an IC ₀₂₅&gt;0 is considered statistically significant. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d415730e300">Findings.</h5> <p id="P10">Using this agnostic approach, we identified multiple CV entities over-reported after ICI treatment compared to the entire database. ICI treatment was associated with higher reporting of myocarditis (n:122, ROR: 11.21 [9.36–13.43], IC ₀₂₅:3.2), pericardial diseases (n:95, ROR: 3.8 [3.08–4.62], IC ₀₂₅:1.63), and vasculitis (n:82, ROR: 1.56 [1.25–1.94], IC ₀₂₅:0.03), including temporal-arteritis (n:18, ROR: 12.99 [8.12–20.77], IC ₀₂₅:2.59). These CV-irAE affected mostly men (58–67%), with a wide age range (20–90 years) and occurred early after ICI administration (40–80% within one month of first ICI administration). Pericardial disorders were reported more often in patients with lung cancer (56.3%) whereas myocarditis and vasculitis were more commonly reported in patients with melanoma (40.7% and 60%, respectively; p&lt;0.001). Vision was impaired in 27.8% of temporal-arteritis cases. CV-irAE were serious in the majority of cases (&gt;80%), with fatalities occurring in 50% of myocarditis cases, 21.1% of pericardial disorders and 6.1% of vasculitis (p&lt;0.0001). Among myocarditis cases, fatality was most frequent in ICI combination therapy compared to ICI monotherapy (65.6% vs. 44.4%, p:0.04). </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d415730e317">Interpretation.</h5> <p id="P11">ICI may lead to severe and disabling inflammatory CV-irAEs early during therapy. Besides life-threatening myocarditis, these toxicities include pericardial disorders, as well as temporal arteritis with a risk for blindness. </p> </div>