What Bruton's Tyrosine Kinase (BTK) inhibitor has the safest cardiac profile?

From the Guidelines

Acalabrutinib or zanubrutinib are preferred over ibrutinib due to their safer cardiac profile, with less atrial fibrillation and less hypertension, especially in older patients or those with cardiovascular disease. When considering the safest cardiac profile among Bruton's Tyrosine Kinase (BTK) inhibitors, it's essential to weigh the risks and benefits of each option. According to the most recent evidence from 2024, acalabrutinib and zanubrutinib have demonstrated a lower incidence of cardiac adverse events compared to ibrutinib 1.

Key Considerations

• Acalabrutinib and zanubrutinib have shown lower rates of atrial fibrillation, with 4.1% and 3.2% of patients experiencing this condition, respectively, compared to ibrutinib 1.
• The mechanisms behind ibrutinib-associated atrial fibrillation are not fully understood but may be related to off-target inhibition of cardiac Tec protein kinase and PI3K, as well as abnormal Ca2+ handling 1.
• Newer BTK inhibitors like acalabrutinib and zanubrutinib, with higher BTK selectivity, present a lower incidence of atrial fibrillation than ibrutinib 1.

Clinical Implications

• Patients with pre-existing cardiovascular conditions should be closely monitored when taking any BTK inhibitor.
• Acalabrutinib or zanubrutinib may be preferred over ibrutinib in patients with an increased risk of cardiac toxicity, due to their safer cardiac profile.
• The treatment of ibrutinib-induced atrial fibrillation can be complicated due to the drug's antiplatelet properties and potential interactions with other medications used to manage atrial fibrillation 1.

Recommendation

In patients requiring BTK inhibitor therapy, acalabrutinib or zanubrutinib should be considered as the first-line option due to their safer cardiac profile, especially in those with pre-existing cardiovascular conditions or at increased risk of cardiac toxicity 1.

From the FDA Drug Label

At a dose 4 times the approved recommended dosage, CALQUENCE does not prolong the QTc interval to any clinically relevant extent. At the approved recommended doses (160 mg twice daily or 320 mg once daily), there were no clinically relevant effects on the QTc interval.

Based on the information provided, acalabrutinib and zanubrutinib both appear to have a safe cardiac profile, as they do not prolong the QTc interval to a clinically relevant extent at their recommended doses or even at higher doses in the case of acalabrutinib. However, acalabrutinib may be considered to have a slightly safer cardiac profile due to the additional information provided about its effects on the QTc interval at a dose 4 times the approved recommended dosage 2.

From the Research

Cardiac Safety Profile of BTK Inhibitors

The cardiac safety profile of Bruton's Tyrosine Kinase (BTK) inhibitors is a crucial consideration in the treatment of B-cell malignancies. Several studies have investigated the cardiac risks associated with these agents.

Comparison of BTK Inhibitors

• Acalabrutinib has been shown to have a lower incidence of cardiac adverse events compared to ibrutinib, with a pooled analysis of 762 patients reporting cardiac AE of any grade in 17% of patients, and grade ≥3 cardiac AE in 5% of patients 3.
• Zanubrutinib has also demonstrated a favorable cardiac safety profile, with a phase 2 study reporting atrial fibrillation in only 4% of patients, and no grade 4 intolerance events or treatment-related deaths 4.
• A pharmacovigilance analysis of cardiac risks associated with BTK inhibitors found that acalabrutinib had statistically significant lower reporting of cardiac events compared to ibrutinib, with atrial fibrillation being the most commonly reported cardiac event 5.
• A combined analysis of the impact of second-generation BTK inhibitors on patient outcomes found that acalabrutinib and zanubrutinib were associated with significant reductions in cumulative event rates of atrial fibrillation, hypertension, bleeding, diarrhea, and infections compared to ibrutinib 6.

Cardiac Risks Associated with BTK Inhibitors

• Atrial fibrillation is a common cardiac adverse event associated with BTK inhibitors, with ibrutinib posing the highest risk 5.
• Hypertension is also a common cardiac adverse event associated with BTK inhibitors, with acalabrutinib and zanubrutinib having a lower incidence of hypertension compared to ibrutinib 7, 6.
• Ventricular arrhythmias are a rare but potentially life-threatening cardiac adverse event associated with BTK inhibitors, with ibrutinib posing a higher risk compared to acalabrutinib and zanubrutinib 7.