What are the cardiac effects of Opdivo (nivolumab)?

Cardiac Effects of Opdivo (Nivolumab)

Nivolumab can cause potentially fatal cardiac immune-related adverse events (irAEs), most notably myocarditis, which has a high mortality rate of 23% even with prompt treatment. 1

Overview of Cardiac Toxicities

Nivolumab-associated cardiac toxicities include:

• Myocarditis: The most serious cardiac irAE

  • Prevalence: 1.14% of patients 1
  • Median onset: 34 days from treatment initiation 1
  • Higher risk with combination therapy (anti-PD-1 + anti-CTLA-4)
  • Often co-occurs with myositis and myasthenia gravis 1

• Other cardiac manifestations:

  • Pericarditis
  • Arrhythmias (ventricular and supraventricular)
  • Cardiomyopathy
  • Cardiac fibrosis
  • Heart failure
  • Cardiac arrest 1

Risk Factors

Several factors increase the risk of nivolumab-induced cardiac toxicity:

• Combination immunotherapy (nivolumab + ipilimumab) carries higher risk than monotherapy 1
• Diabetes mellitus 1
• Early treatment phase (64% of myocarditis cases occur after only 1-2 doses) 1
• Pre-existing cardiovascular disease 1

Clinical Presentation

Cardiac irAEs often present with nonspecific symptoms that can be easily overlooked:

• Shortness of breath
• Chest pain
• Myalgia
• Fatigue
• Palpitations
• Edema 1, 2

In fatal cases, conduction abnormalities are the common mode of death, often with preserved ejection fraction 1.

Diagnostic Approach

When cardiac toxicity is suspected, immediate evaluation should include:

1. Cardiology consultation and ICU-level monitoring 1
2. Laboratory testing:
   • Cardiac biomarkers (creatine kinase, troponin)
   • Inflammatory markers (ESR, CRP, WBC count) 1
3. Cardiac monitoring:
   • Telemetry
   • Electrocardiogram 1
4. Imaging:
   • Echocardiogram
   • Cardiac MRI when feasible 1
5. Consider biopsy in severe cases 1

Management

Management depends on severity but requires prompt intervention:

• Grade 2-3 cardiac toxicities:

  • May continue nivolumab with close monitoring
  • Cardiology consultation 3

• Grade 4 cardiac toxicities or suspected myocarditis:

  • Permanently discontinue nivolumab
  • Admit for intensive monitoring
  • Immediate high-dose corticosteroids
  • Respiratory and hemodynamic support as needed
  • Consider additional immunosuppressive drugs if not responding to steroids 3

Elevated troponin levels ≥1.5 ng/mL are associated with a 4-fold increased risk of major adverse cardiac events, and higher-dose corticosteroids have shown better treatment response in these cases 1.

Comparative Risk

While both nivolumab and pembrolizumab can cause cardiac toxicities, some evidence suggests differences in their risk profiles:

• Nivolumab accounts for 55.7% of reported cardiotoxicity cases versus 27.31% for pembrolizumab 4
• However, myocarditis specifically appears more likely with pembrolizumab therapy 4

Case Reports and Mortality

Several case reports highlight the potential severity of nivolumab-induced cardiac toxicity:

• Fatal myocarditis despite intensive support 5
• Nivolumab-related myasthenia gravis with myositis and myocarditis requiring prolonged mechanical ventilation 6
• Fatal active myocarditis presenting as acute right-sided heart failure 7

Clinical Implications

1. Baseline cardiac evaluation before initiating nivolumab
2. Regular monitoring during treatment, especially during the first few cycles
3. Prompt recognition of cardiac symptoms, even if nonspecific
4. Immediate intervention with high-dose corticosteroids if cardiac toxicity is suspected
5. Multidisciplinary approach involving oncology and cardiology

Pitfalls to Avoid

• Delayed recognition: Symptoms of cardiac toxicity can be nonspecific and easily attributed to other causes
• Inadequate monitoring: Cardiac toxicity can develop rapidly, often after just 1-2 doses
• Insufficient treatment: High-dose steroids are needed for suspected myocarditis
• Failure to discontinue therapy: Grade 4 cardiac toxicities require permanent discontinuation of nivolumab
• Missing co-occurring irAEs: Cardiac toxicity often co-occurs with myositis and myasthenia gravis

In summary, while nivolumab is an effective cancer treatment, its potential cardiac effects require vigilance, prompt recognition, and aggressive management to prevent fatal outcomes.