Can Ibrutinib (ibrutinib) cause cardiotoxicity?

Ibrutinib and Cardiotoxicity

Yes, ibrutinib definitively causes cardiotoxicity, with atrial fibrillation being the most common cardiac adverse effect, occurring in 3-16% of patients, and hypertension affecting up to 20% of patients. 1

Types of Cardiotoxicity Associated with Ibrutinib

Atrial Fibrillation

• Incidence ranges from 3-16% of patients treated with ibrutinib, depending on:
  • Patient population characteristics
  • Length of follow-up (risk increases over time)
  • Method of detection 1
• Timing: 76% of cases occur within the first year of therapy (median onset: 3.8 months) 1
• Presentation: Paroxysmal in 64% of cases, with 42% being symptomatic and requiring urgent medical intervention (grade 3-4) 1
• Risk factors: Pre-existing cardiovascular disease increases risk nearly threefold (17% vs 7%) 2

Hypertension

• Occurs in up to 20% of patients treated with ibrutinib 1
• Often develops within 1 month of treatment initiation 3
• Significant increases in both systolic and diastolic blood pressure compared to baseline 3

Myocardial Injury

• Recent evidence shows diffuse myocardial injury (inflammation and fibrosis) in patients treated with ibrutinib 4
• Cardiovascular magnetic resonance imaging shows:
  • Late gadolinium enhancement (indicating fibrosis) in 54.8% of treated patients
  • Elevated native T1 and max-T2 values, suggesting ongoing inflammation 4

Mechanisms of Ibrutinib-Induced Cardiotoxicity

The mechanisms of ibrutinib-associated cardiotoxicity are not fully established but likely include:

• Off-target inhibition of cardiac Tec protein kinase and PI3K (both regulated by BTK)
• Enhanced cardiac automaticity related to abnormal calcium handling 1
• Diffuse myocardial inflammation and fibrosis as demonstrated by cardiac MRI 4

Clinical Implications and Management

Risk Assessment

• Screen for pre-existing cardiovascular disease before initiating ibrutinib 2
• Patients with pre-existing cardiovascular disease have:
  • Higher rates of atrial arrhythmias (17% vs 7%)
  • Increased adjusted all-cause mortality (OR 1.9,95% CI 1.06-3.41)
  • Decreased survival probability (43% vs 54%) 2

Monitoring and Management

• Monitor for atrial fibrillation and hypertension in all patients on ibrutinib 1
• Consider cardiac MRI in patients with suspected cardiotoxicity, as presence of late gadolinium enhancement is associated with higher risk of major adverse cardiac events (HR 4.9) 4
• For patients who develop atrial fibrillation:
  • Exercise caution with anticoagulation due to ibrutinib's antiplatelet properties 1
  • Be aware of drug interactions between ibrutinib and medications used to manage AF (amiodarone, digoxin, diltiazem, verapamil, anticoagulants) 1
• For hypertension:
  • Monitor blood pressure regularly, especially within the first month of treatment 3
  • Initiate or adjust antihypertensive therapy promptly when blood pressure elevations occur 3

Alternative BTK Inhibitors

• Newer generation BTK inhibitors (acalabrutinib, zanubrutinib) with higher BTK selectivity show lower incidence of cardiotoxicity:
  • Acalabrutinib: 4.1% atrial fibrillation rate
  • Zanubrutinib: 3.2% atrial fibrillation rate 1
• Real-world data confirms significantly lower incidence of new-onset atrial fibrillation with acalabrutinib compared to ibrutinib (4.6% vs 17%) 5

Practical Recommendations

1. Perform cardiovascular risk assessment before initiating ibrutinib
2. Consider alternative BTK inhibitors (acalabrutinib, zanubrutinib) in patients with pre-existing cardiovascular disease
3. Monitor blood pressure at baseline and regularly during treatment, especially in the first month
4. Implement early management of hypertension when detected
5. Maintain vigilance for symptoms of atrial fibrillation
6. Use caution with anticoagulation in patients who develop atrial fibrillation
7. Consider holding ibrutinib 3-7 days before and after surgical procedures due to bleeding risk 1

Cardiotoxicity from ibrutinib is manageable in most cases and should not necessarily lead to drug discontinuation, but requires careful monitoring and prompt intervention when detected.