Real-World Adverse Event Profile of Pirtobrutinib: A Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System with a Focus on Cardiovascular Safety Relative to Ibrutinib

Pirtobrutinib (Jaypirca) is the first non-covalent, reversible Bruton tyrosine kinase (BTK) inhibitor approved for mantle cell lymphoma and chronic lymphocytic leukemia (CLL). Its covalent predecessors, particularly ibrutinib, carry cardiovascular toxicity, notably atrial fibrillation (AF) and hypertension. Pirtobrutinib has greater kinase selectivity that is hypothesized to cause much less off-target cardiovascular toxicity than covalent BTK inhibitors; however, supporting evidence is largely derived from clinical trials. Earlier FDA Adverse Event Reporting System (FAERS, renamed the Adverse Event Monitoring System in March 2026) analyses excluded pirtobrutinib for insufficient post-marketing data. Three years after approval, we tested this against real-world reports. Ibrutinib (the first BTK inhibitor approved in the US) was selected as the comparator given its well-established cardiovascular toxicity profile.

We analyzed FAERS data from 2023 Q1, the quarter of pirtobrutinib's US approval, through 2026 Q1. After deduplication, reports listing pirtobrutinib as primary suspect were identified. Disproportionate reporting was assessed with the reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC). A signal required an ROR lower CI above 1, PRR ≥2 with chi-squared statistic ≥4, IC025 >0, and ≥3 cases. A predefined cardiovascular analysis compared pirtobrutinib against the database, then ibrutinib. Sensitivity analyses varied suspect role, reporter type, and co-reported BTK inhibitors. The protocol was registered on Open Science Framework (osf.io/n37b4) before data extraction.

We identified 459 pirtobrutinib and 15,613 ibrutinib primary suspect reports. Median age was 74 years, predominantly male, mostly with mantle cell lymphoma or CLL. The analysis recovered pirtobrutinib's expected pharmacology: redistribution lymphocytosis (ROR 140.3), tumour lysis syndrome (ROR 21.1), cytopenias, pneumonia (ROR 3.1), and contusion (ROR 3.9), all meeting the signal criteria. Against ibrutinib, AF was reported five times less often (0.9% vs 4.4%; ROR 0.19, 95% CI 0.07 to 0.51), and the difference persisted when secondary-suspect reports were added (ROR 0.29, 95% CI 0.14 to 0.57). Hypertension pointed the same way, 1 case vs 433, but fell below the three-case threshold. Cardiac failure was reported more often (ROR 2.20, 95% CI 1.07 to 4.52), as was cardiac arrest on secondary-suspect analysis. Ibrutinib reproduced its established profile, including AF (ROR 11.19), confirming comparator validity.

To our knowledge, this is the first study using FAERS to evaluate the cardiovascular safety profile of pirtobrutinib relative to ibrutinib. AF reporting was substantially lower than with ibrutinib, a difference that held across sensitivity analyses and provides the first post-marketing evidence for the proposed cardiovascular advantage of non-covalent BTK inhibition. Hypertension trended similarly, however a formal signal assessment was not possible due to only one report attributed to pirtobrutinib. Cardiac failure and cardiac arrest were reported more frequently with pirtobrutinib, potentially reflecting differences in treatment line, disease burden, or baseline cardiovascular risk not captured within FAERS. These are spontaneous reports, subject to notoriety and channeling bias, and do not reflect incidence. Even with these limits, the findings support a lower reporting frequency of AF with pirtobrutinib compared to ibrutinib and provide post-marketing evidence suggesting a more favorable cardiovascular profile, warranting prospective comparison.