Ibrutinib, a first-generation Bruton's tyrosine kinase inhibitor, has transformed the treatment of B-cell malignancies, including chronic lymphocytic leukemia. Despite its efficacy, concerns have emerged regarding cardiovascular and hemorrhagic toxicities, particularly atrial fibrillation and bleeding events. Understanding the magnitude of these risks is essential to guide clinical decision-making, optimize patient monitoring, and compare Ibrutinib’s safety profile with that of newer BTK inhibitors. Furthermore, given the increasing use of BTK inhibitors in earlier treatment lines, assessing their long-term safety is critical for balancing therapeutic benefits and potential harms.

To assess the incidence and relative risk of atrial fibrillation and bleeding associated with Ibrutinib, compare with other BTK inhibitors, and identify patient factors influencing these adverse events.

A PubMed search was conducted to identify systematic reviews, meta-analyses, and network meta-analyses published between 2020 and 2025, combining the drug name Ibrutinib with terms related to atrial fibrillation (including “AF”) and bleeding events (including “hemorrhage” and “bleeding diathesis”). Filters were applied to restrict results to the selected study types. Two reviewers independently screened all records, including studies reporting quantitative efficacy and/or safety data in patients treated with Ibrutinib. A total of 51 articles met the inclusion criteria for qualitative and quantitative synthesis.

Ibrutinib treatment is consistently linked to increased risks of atrial fibrillation (AF) and bleeding events. AF incidence ranges from 6–16% in clinical trials and up to 18% in real-world CLL cohorts; notable rates include 16.0% in ELEVATE-RR, 9.2% in an Italian study, 13.9% overall arrhythmia, and 14.8% in older CLL patients. Risk is significantly higher than with chemoimmunotherapy (OR 4.95; HR 4.92; HR 2.37; AOR 1.48; HR 1.47). Pre-existing cardiovascular disease increases AF risk and mortality. Compared to Ibrutinib, acalabrutinib shows lower AF incidence (5.2–9.4% vs. 16.0%; HR 0.54), with zanubrutinib, orelabrutinib, and tirabrutinib (2.9%) also showing reduced rates. Major bleeding occurs in 1–8% of patients, all-grade bleeding in 2–50%. Real-world data show 3.1–7% major bleeding, 3.6% grade ≥ 3 events in Spain, and 13.5% in older CLL patients. Risk is elevated versus non-Ibrutinib controls (AOR 1.71; HR 1.55; HR 1.41). Concomitant anticoagulation further increases bleeding risk, often necessitating treatment discontinuation. Acalabrutinib demonstrates fewer major hemorrhages (2.0% vs. 3.9%; HR 0.53); zanubrutinib and orelabrutinib also show favorable bleeding profiles. Collectively, these findings indicate that while Ibrutinib remains a highly effective agent, its toxicity profile demands proactive surveillance and individualized therapeutic strategies. Ibrutinib use is consistently associated with a significantly increased risk of atrial fibrillation and bleeding events, as shown in both clinical trials and real-world studies. The magnitude of risk is higher than with chemoimmunotherapy and generally greater than with newer BTK inhibitors, which demonstrate more favorable safety profiles. These findings highlight the importance of careful cardiovascular and bleeding risk assessment, close monitoring, and consideration of alternative agents to optimize patient safety, particularly in high-risk populations and in those requiring long-term therapy.