Did atezolizumab (Tecentriq) and bevacizumab (Avastin) cause atrial fibrillation in a patient with underlying cancer?

Atezolizumab and Bevacizumab Can Cause Atrial Fibrillation, Though the Risk is Relatively Low

While atezolizumab (an immune checkpoint inhibitor) has documented associations with atrial fibrillation, the absolute risk remains low at approximately 0.62-2.1%, and bevacizumab is not specifically identified as a high-risk agent for drug-induced AF. However, the combination of these agents in a cancer patient creates a complex clinical scenario where multiple factors—the cancer itself, the drugs, and patient comorbidities—may all contribute to AF development 1.

Evidence for Atezolizumab-Associated AF

Atezolizumab (anti-PD-L1 agent) is specifically associated with arrhythmic adverse events among immune checkpoint inhibitors:

• In a real-world FAERS database analysis, most arrhythmic adverse events occurred in patients treated with anti-PD-1 (nivolumab) and anti-PD-L1 drugs including atezolizumab and avelumab, while anti-CTLA-4 agents showed no significant association 1

• Among patients who develop ICI-related myocarditis or cardiotoxicity, AF was observed in 26-30% of them, though ICI-induced cardiotoxicity itself only occurs in 1-5% of patients 1

• In a retrospective cohort of 12,187 advanced cancer patients on ICI treatment, AF was present in 250 patients (2.1%) 1

• A pharmacovigilance study using VigiBase found AF/atrial flutter represented 88% of reported supraventricular arrhythmias and were significantly more often reported in ICI-treated patients than those on other anticancer drugs (0.71% vs 0.42%) 1

Evidence for Bevacizumab

Bevacizumab is not listed among the 19 anticancer drugs significantly associated with AF in the WHO's VigiBase database analysis, nor does it appear in major reviews of AF-inducing anticancer drugs 1. The highest-risk agents identified were ibrutinib (reporting OR 8.99), IL-2 (5.01), and nilotinib (3.92) 1.

The Cancer Itself as a Confounding Factor

A critical clinical challenge is determining whether AF reflects the baseline state of the patient, the cancer itself, or an adverse drug effect:

• Active cancer is independently associated with AF risk factors including advanced age (~60% of patients >65 years), systemic inflammation, electrolyte abnormalities, metabolic and endocrine disturbances, and increased sympathetic tone 1, 2

• Cancer patients with new-onset AF have significantly higher morbidity and mortality compared to those without AF (OR 1.90; 95% CI 1.65-2.19; P < 0.0001) 1, 2

• Hematologic malignancies, intrathoracic cancers (lung, esophageal), and CNS cancers are associated with >2-fold increased AF risk compared to non-cancer controls 1, 2

• Unfortunately, because baseline ECGs prior to anticancer drug initiation are often missing in clinical trials, it is difficult to ascertain between these possibilities 1

Algorithmic Approach to Causality Assessment

To determine if atezolizumab/bevacizumab caused the AF in your patient, systematically evaluate:

1. Temporal relationship: Did AF develop within 2-8 months of starting therapy? (Most ICI-associated AF occurs within the first year) 1

2. Baseline cardiovascular status: Was there a pre-treatment ECG showing normal sinus rhythm? Were there pre-existing AF risk factors (age >65, hypertension, heart failure, valvular disease)? 1

3. Cancer-related factors: Does the patient have a hematologic malignancy, lung cancer, or esophageal cancer (higher AF risk)? Is there evidence of systemic inflammation, electrolyte abnormalities, or paraneoplastic conditions? 1, 2

4. ICI-related cardiotoxicity: Are there signs of ICI-induced myocarditis (elevated troponin, new LV dysfunction, chest pain)? If myocarditis is present, the likelihood of ICI-caused AF increases substantially to 26-30% 1

5. Other medications: Is the patient on other QT-prolonging or arrhythmogenic drugs? 1

Management Implications

Do not discontinue atezolizumab or bevacizumab solely because of AF:

• The presence of AF does not represent a contraindication to anticancer drug treatment, and drug discontinuation must be exceptional and weighed against cancer progression risk 1, 3

• AF is generally manageable with continuation of anticancer drugs; interruption must be avoided whenever possible 3

• In patients with CLL developing AF on ibrutinib (the highest-risk agent), those who interrupted treatment had decreased progression-free survival compared to those who continued (median 19 vs 27 months, P = 0.023) 1

Follow standard AF management guidelines with cardio-oncology modifications:

• Initiate rate control with beta-blockers as first-line therapy 3

• Consider rhythm control if symptoms persist despite optimal rate control 1, 3

• Evaluate thromboembolic risk using the "TBIP" approach (Thromboembolic risk, Bleeding risk, drug-drug Interactions, Patient preferences) rather than standard CHA₂DS₂-VASc alone 3

• Cancer patients with AF have a 2-fold higher risk of systemic thromboembolism/stroke and 6-fold higher risk of heart failure 3

Critical Pitfalls to Avoid

Do not assume the drugs are solely responsible without evaluating the cancer's contribution 1. Many anticancer drugs produce AF when they add to or aggravate pre-existing and/or cancer-related pro-AF factors, working additively or synergistically rather than as sole causative agents 4.

Do not delay anticoagulation decisions 3, 5. Patients with active cancer and AF have particularly high thromboembolic risk from both conditions, and physicians' reluctance to prescribe anticoagulants due to bleeding fears is often excessive relative to actual risk 5.

Ensure cardiovascular evaluation before continuing therapy 1. In patients requiring potentially cardiotoxic anticancer drugs with diagnosed AF or risk factors, referral to a cardiologist is recommended before continuing treatment 1.