What are the management considerations for a patient with a history of cancer, currently being treated with atezolizumab (anti-programmed death-ligand 1 (PD-L1) antibody) and bevacizumab (vascular endothelial growth factor (VEGF) inhibitor), who also has atrial fibrillation (Afib)?

Management of Atrial Fibrillation in Patients Receiving Atezolizumab and Bevacizumab

For cancer patients on atezolizumab plus bevacizumab who develop atrial fibrillation, prioritize rate control with beta-blockers (target heart rate <110 bpm) over rhythm control, implement individualized anticoagulation based on bleeding versus thrombotic risk assessment, and continue cancer therapy whenever possible while coordinating with cardio-oncology. 1

Rate Control as First-Line Strategy

Rate control is preferable to rhythm control in asymptomatic or hemodynamically stable cancer patients with atrial fibrillation, as spontaneous recovery to sinus rhythm may occur and antiarrhythmic drugs have limited efficacy when the causative cancer drug continues. 1

• Target resting heart rate should be <110 beats per minute 1
• Beta-blockers are the preferred rate-control agents, particularly in patients with reduced left ventricular ejection fraction or heart failure 1
• Diltiazem may be preferred over verapamil in patients with preserved ejection fraction due to lower risk of symptomatic hypotension 1
• Avoid diltiazem and verapamil in patients with reduced ejection fraction due to negative inotropic effects 1
• Critical drug interaction warning: Diltiazem and verapamil inhibit CYP3A4, creating multiple interactions with anticancer drugs and anticoagulants 1
• Use digoxin with extreme caution, as some anticancer drugs inhibit P-glycoprotein, increasing digoxin levels and toxicity risk 1

Rhythm Control Considerations

• Rhythm control should only be pursued when patients remain symptomatic despite adequate rate control 1
• Cardioversion has limited long-term success in cancer patients, with more than two-thirds failing to maintain sinus rhythm when the causative drug continues 1
• Weak evidence supports amiodarone use in cancer patients, though it carries risks of pulmonary toxicity and multiple drug interactions 1
• Catheter ablation has higher periprocedural complications, in-hospital mortality, and bleeding-related readmissions in cancer patients 1
• Ablation may be considered only in highly symptomatic patients despite medical therapy or to avoid potentially fatal drug-drug interactions, requiring multidisciplinary team discussion 1

Anticoagulation Strategy: The Critical Balance

Cancer patients with atrial fibrillation face a dual challenge: cancer itself creates a prothrombotic state with twofold higher thromboembolism risk, while simultaneously increasing bleeding risk through tumor type, thrombocytopenia, and coagulation defects. 1, 2, 3

Thrombotic Risk Assessment

• Atrial fibrillation in cancer patients is associated with a twofold higher risk of systemic thromboembolism or stroke 2, 3
• Bevacizumab (VEGF inhibitor) specifically increases thromboembolic risk as an angiogenesis inhibitor 1
• Pancreatic, ovarian, lung, and primary hepatic cancers carry particularly high thrombotic risk 1
• Immobility and advanced age create additive thrombotic risk in this population 2

Bleeding Risk Assessment

• Bevacizumab significantly increases bleeding risk, with hypertension occurring in 26-30% and proteinuria in 10-20% of patients 1, 4, 5
• Intracranial, gastrointestinal, and genitourinary cancers have inherently higher bleeding risk 1
• Chemotherapy-induced thrombocytopenia and coagulation defects from hematological malignancies increase bleeding 1
• Patients must undergo endoscopic evaluation and treatment for esophageal varices before initiating bevacizumab 1

Anticoagulant Selection

Anticoagulation should follow ESC guidelines with cancer-specific modifications, weighing thrombotic risk against bleeding risk. 1

• Direct oral anticoagulants (DOACs) are generally preferred over warfarin in cancer patients with atrial fibrillation when no contraindications exist 6, 7
• DOACs demonstrate 51% reduction in intracranial hemorrhage compared to warfarin 6, 7
• DOACs reduce stroke/systemic embolic events by 19% (RR 0.81; 95% CI 0.73-0.91) 6, 7
• However, warfarin may be preferred in patients with luminal gastrointestinal cancers with intact primary or active gastrointestinal mucosal abnormalities due to higher DOAC bleeding risk 6

Critical Drug Interactions with Anticoagulants

• Bevacizumab does not have direct pharmacokinetic interactions with DOACs or warfarin, but increases bleeding risk through vascular effects 5, 8
• Atezolizumab does not have direct drug interactions with anticoagulants 5, 8
• Monitor for medications that inhibit P-glycoprotein and CYP3A4, which can increase DOAC levels 6, 8
• CHA2DS2-VASc and HAS-BLED scores have not been fully validated in cancer populations but should still guide decision-making 1

Cancer Treatment Continuation

Cancer treatment interruption due to atrial fibrillation should be avoided whenever possible and must be discussed with the cardio-oncology team. 1

• Atezolizumab plus bevacizumab significantly improves overall survival and progression-free survival in hepatocellular carcinoma (median PFS 6.8 months vs 4.3 months with sorafenib; HR 0.59) 1, 5
• The combination demonstrates manageable toxicity profile with hypertension (26-30%), proteinuria (10-20%), and fatigue (15-20%) as most common adverse events 1, 4, 5
• Treatment discontinuation should only occur for unacceptable toxicities, not for manageable atrial fibrillation 1
• Coordinate with cardio-oncology to optimize cardiovascular management while maintaining cancer therapy 1

Monitoring Requirements

• Assess blood pressure at every visit due to bevacizumab-induced hypertension risk (26-30% incidence) 1, 4, 5
• Monitor proteinuria regularly (occurs in 10-20% of patients on bevacizumab) 1, 4, 5
• Evaluate for bleeding symptoms at each encounter given dual bleeding risk from cancer and bevacizumab 1, 5
• Renal function should be assessed at least annually if on DOACs 7
• Monitor heart rate control with goal <110 bpm at rest 1

Special Considerations for Bevacizumab

• Bevacizumab must be held 3-7 days before invasive procedures due to bleeding risk 1
• Patients with inadequately controlled hypertension should not receive bevacizumab 1
• Gastroesophageal varices must be treated before initiating bevacizumab due to high bleeding risk 1
• Current or recent use of therapeutic antiplatelet agents or thrombolytics requires careful risk-benefit assessment 1

Left Atrial Appendage Occlusion

• May be considered for stroke prevention in cancer patients with atrial fibrillation who have contraindications to long-term anticoagulation and life expectancy >12 months 1
• Requires multidisciplinary team discussion due to device-related thrombosis risk and procedural complications 1
• Limited prospective data exist in cancer populations 1