What is the risk of heart failure in patients using Tumor Necrosis Factor (TNF) inhibitors?

Risk of Heart Failure in Patients Using TNF Inhibitors

TNF inhibitors are absolutely contraindicated in patients with severe heart failure (NYHA class III or IV) due to documented increased mortality and hospitalization rates, and should be avoided or used with extreme caution in mild-to-moderate heart failure (NYHA class I-II) with mandatory cardiac monitoring. 1

Absolute Contraindications

TNF antagonist therapy must be avoided in patients with severe (NYHA class III and IV) cardiac failure. 1 This recommendation stems from clinical trial evidence showing:

• High-dose infliximab (10 mg/kg) was associated with increased mortality in severe heart failure patients, leading to premature trial discontinuation 1, 2
• Etanercept trials in severe CHF were terminated early due to lack of efficacy or failure to show benefit on CHF morbidity or mortality 1
• The combined risk of death or hospitalization through 28 weeks was significantly increased (hazard ratio 2.84) in patients receiving 10 mg/kg infliximab 2

Risk in Mild-to-Moderate Heart Failure

For patients with well-compensated heart failure (NYHA class I and II):

• Obtain a screening echocardiogram before initiating TNF antagonist therapy 1
• Do not initiate TNF antagonist therapy if ejection fraction is <50% of normal 1
• Withdraw treatment immediately at the onset of new symptoms or worsening of pre-existing heart failure 1

Evidence of New-Onset Heart Failure

TNF inhibitors can induce new-onset heart failure even in patients without pre-existing cardiac disease:

• 47 spontaneous FDA reports documented new-onset or worsening heart failure following infliximab or etanercept 1
• 50% of patients with new-onset heart failure had no identifiable pre-existing risk factors for heart disease 1, 3
• Median onset of symptoms was 3 months with infliximab and 8.5 months with etanercept 1
• Complete resolution or substantial improvement occurred after drug withdrawal in younger patients (<50 years) 1, 3

FDA Drug Label Warnings

The FDA-approved labels for TNF inhibitors explicitly warn:

• "Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers" 4, 5
• "Exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully" 5
• "Call your healthcare provider right away if you get new or worsening symptoms of heart failure while taking Enbrel, such as shortness of breath or swelling of your lower legs or feet" 4

Alternative Biologic Options for Patients with Heart Failure

When TNF inhibitors are contraindicated due to heart failure:

• The American College of Rheumatology conditionally recommends IL-17 inhibitors or IL-12/23 inhibitors (ustekinumab) as preferred alternatives 1, 6
• These agents do not carry the same cardiac contraindications as TNF inhibitors 6

Dose-Dependent Effects

The cardiac risk appears dose-dependent:

• Standard therapeutic doses may have less cardiac risk than high doses 7
• High-dose infliximab (10 mg/kg) showed significantly worse outcomes compared to lower doses (5 mg/kg) 2
• There is insufficient evidence to support TNF inhibitor use at any dose in severe heart failure 8, 7

Monitoring Requirements

For any patient on TNF inhibitors with cardiac risk factors:

• Monitor closely for signs of heart failure development: shortness of breath, lower extremity edema, exercise intolerance, fatigue 4, 5
• Discontinue TNF inhibitor immediately if new cardiac symptoms develop 1
• Consider baseline and periodic echocardiography in patients with NYHA class I-II disease 1

Critical Clinical Pitfall

Do not assume that clinical trial data showing "no excess risk" in psoriasis or rheumatoid arthritis populations accurately reflects real-world cardiac safety, as these trials systematically excluded patients with significant heart failure, creating selection bias 1