What is the preferred treatment between hydroxychloroquine (HCQ) and sulfasalazine (SSZ) for patients with rheumatoid arthritis (RA) and cardiac failure?

Hydroxychloroquine is Preferred Over Sulfasalazine in RA Patients with Cardiac Failure

For patients with rheumatoid arthritis and cardiac failure, hydroxychloroquine should be used preferentially over sulfasalazine, and both TNF inhibitors and sulfasalazine should be avoided in favor of non-TNF biologic DMARDs or targeted synthetic DMARDs. 1

Primary Recommendation for Heart Failure

• Addition of a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over addition of a TNF inhibitor for patients with NYHA class III or IV heart failure and inadequate response to conventional synthetic DMARDs. 1

• Switching to a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over continuation of a TNF inhibitor for patients taking a TNF inhibitor who develop heart failure. 1

• The 2021 ACR guidelines specifically address cardiac failure as a contraindication to TNF inhibitor therapy, making non-TNF biologics (abatacept, rituximab, tocilizumab) or JAK inhibitors the preferred advanced therapies. 1

Hydroxychloroquine vs Sulfasalazine: Direct Comparison

Why Hydroxychloroquine is Preferred

• Hydroxychloroquine is conditionally recommended over other conventional synthetic DMARDs because it is better tolerated and has a more favorable risk profile in patients with RA. 1, 2

• When tapering triple therapy, gradual discontinuation of sulfasalazine is conditionally recommended over gradual discontinuation of hydroxychloroquine due to sulfasalazine's poorer treatment persistence from adverse events. 1

• This recommendation implicitly favors maintaining hydroxychloroquine over sulfasalazine when choosing between the two agents. 1

Cardiovascular Safety Profile of Hydroxychloroquine

The cardiovascular risk data for hydroxychloroquine in heart failure patients shows important nuances:

• In patients with pre-existing heart failure, hydroxychloroquine was associated with increased risk of MACE (HR 1.30), cardiovascular mortality (HR 1.34), all-cause mortality (HR 1.22), myocardial infarction (HR 1.74), and hospitalized heart failure (HR 1.29) compared to methotrexate. 3

• However, hydroxychloroquine did not increase risk of sudden cardiac arrest or ventricular arrhythmia (HR 1.03) compared to methotrexate. 3

• A large multinational study found no excess risk of severe adverse events with 30-day hydroxychloroquine use compared to sulfasalazine, though long-term use showed increased cardiovascular mortality (HR 1.65). 4

• A nationwide cohort study found hydroxychloroquine did not increase the risk of cardiac arrhythmia in patients with RA, SLE, or Sjögren's syndrome regardless of dose or duration. 5

• One study found no association between hydroxychloroquine use and development of heart failure in RA patients (OR 0.96 per 100g cumulative dose). 6

Critical Safety Considerations for Hydroxychloroquine in Heart Failure

FDA Black Box Warnings

• Fatal and life-threatening cardiomyopathy has been reported with hydroxychloroquine, including cases with ventricular hypertrophy, pulmonary hypertension, and conduction disorders. 7

• Hydroxychloroquine has potential to prolong QT interval, and ventricular arrhythmias including torsades de pointes have been reported. 7

• Avoid hydroxychloroquine in patients with congenital or acquired QT prolongation, cardiac disease including heart failure or myocardial infarction, bradycardia <50 bpm, or uncorrected electrolyte abnormalities. 7

Practical Monitoring Algorithm

Before initiating hydroxychloroquine in a patient with cardiac failure:

• Obtain baseline ECG to assess QTc interval and rule out conduction abnormalities. 7
• Check and correct serum potassium and magnesium levels. 7
• Review all concomitant medications for QT-prolonging agents. 7
• Assess NYHA functional class and ensure heart failure is optimally managed. 1

During treatment:

• Monitor cardiac function as clinically indicated during therapy. 7
• Discontinue hydroxychloroquine if cardiotoxicity is suspected or demonstrated. 7
• The ACR white paper emphasizes that while cardiac toxicity is rare, awareness increases safe use of these medications. 8

Clinical Decision Algorithm

For RA patients with cardiac failure requiring DMARD therapy:

1. If DMARD-naive with low disease activity: Start hydroxychloroquine over sulfasalazine (better tolerated, more favorable risk profile). 1, 2

2. If DMARD-naive with moderate-to-high disease activity: Start methotrexate monotherapy as first-line (strongly recommended over hydroxychloroquine or sulfasalazine). 1

3. If inadequate response to methotrexate: Add non-TNF biologic (abatacept, rituximab, tocilizumab) or tsDMARD rather than TNF inhibitor. 1

4. If currently on TNF inhibitor and develop heart failure: Switch to non-TNF biologic or tsDMARD. 1

5. If considering triple therapy: Include hydroxychloroquine rather than relying solely on sulfasalazine due to better tolerability. 1, 2

Important Caveats

• The evidence comparing hydroxychloroquine directly to sulfasalazine in heart failure patients is very low certainty, requiring careful clinical judgment. 1

• The most concerning finding is that hydroxychloroquine in patients with pre-existing heart failure showed significantly increased cardiovascular risks compared to methotrexate, suggesting methotrexate may be safer if tolerated. 3

• Sulfasalazine has no specific cardiac contraindications in the guidelines, but its poorer tolerability and treatment persistence make it less desirable. 1

• The safest approach in established heart failure may be to optimize methotrexate first, then add non-TNF biologics if needed, while avoiding both TNF inhibitors and using hydroxychloroquine cautiously with appropriate cardiac monitoring. 1, 3