Can Eliquis (apixaban) cause microscopic hematuria?

Can Eliquis Cause Microscopic Hematuria?

Yes, Eliquis (apixaban) can cause microscopic hematuria as a recognized adverse effect of anticoagulation, occurring in 1.4-2.1% of patients in clinical trials. 1

Evidence from FDA Drug Label

The FDA-approved prescribing information for apixaban explicitly lists hematuria as an adverse reaction occurring in ≥1% of patients across multiple clinical trials 1:

• AMPLIFY study (DVT/PE treatment): Hematuria occurred in 1.7% of apixaban-treated patients compared to 3.8% in enoxaparin/warfarin patients 1
• AMPLIFY-EXT study (extended treatment): Hematuria occurred in 1.4% (2.5 mg dose) and 2.1% (5 mg dose) of apixaban patients versus 1.1% in placebo 1
• Hip/knee replacement surgery studies: Hematuria was documented as occurring at frequencies of ≥0.1% 1

The drug label also notes that "blood urine present, occult blood positive, occult blood, red blood cells urine positive" were documented as less common adverse reactions 1

Clinical Significance and Management

Despite being on anticoagulation, hematuria—whether gross or microscopic—frequently indicates underlying urologic pathology that requires thorough evaluation. 2, 3, 4, 5

Key Clinical Findings:

• 30% of patients with anticoagulant-associated hematuria have significant genitourinary pathology, including malignancy, nephrolithiasis, benign prostatic hyperplasia, infection, or structural abnormalities 3
• 7% of patients with gross hematuria on anticoagulation had neoplastic disease in prospective studies 3
• Even patients considered low-risk for urologic disease can harbor early-stage malignancies when hematuria develops on anticoagulation 4

Evaluation Algorithm:

When microscopic hematuria occurs in a patient on apixaban, the following structured approach should be followed 6, 7:

1. Exclude benign transient causes: Repeat urinalysis 48 hours after cessation of menstruation, vigorous exercise, sexual activity, trauma, or viral illness 6

2. Assess for glomerular vs. non-glomerular bleeding 6:

   • Check for proteinuria (>1,000 mg/24 hours suggests glomerular disease) 6
   • Examine for dysmorphic RBCs (>80% suggests glomerular origin) or RBC casts 6
   • Measure serum creatinine 6

3. If glomerular disease suspected: Nephrology referral for evaluation of systemic disease (lupus, vasculitis, IgA nephropathy) or consideration of renal biopsy 6

4. If non-glomerular bleeding (most common with anticoagulation): Complete urologic evaluation including 6, 3, 5:

   • Upper tract imaging (intravenous pyelography, renal ultrasonography, or CT urography) 6, 5
   • Cystoscopy to evaluate bladder and urethra 6, 5
   • Urine cytology if risk factors for malignancy present 6

Management of Bleeding on Apixaban:

For microscopic hematuria without hemodynamic compromise, apixaban does not need to be discontinued during evaluation 7. However, the American College of Cardiology recommends 7:

• Assess bleeding severity: Microscopic hematuria typically does not meet criteria for major bleeding (hemoglobin drop ≥2 g/dL, transfusion ≥2 units, critical site bleeding, or hemodynamic instability) 7
• If gross hematuria develops: Temporarily discontinue apixaban and provide supportive care 7
• Before restarting anticoagulation: Ensure the bleeding source has been identified and addressed, assess rebleeding risk, and confirm continued indication for anticoagulation 7
• Timing of restart: Once bleeding is controlled, apixaban can be resumed at least 6 hours after hemostasis is achieved 7

Important Caveats

The presence of anticoagulation does not explain away hematuria as a benign finding. 2, 3, 4, 5 Common pitfalls include:

• Attributing hematuria solely to anticoagulation without investigation, potentially missing early malignancy 4
• Assuming therapeutic INR levels (for warfarin) or appropriate apixaban dosing means hematuria is expected—significant pathology is still present in 30% of cases 3
• Delaying evaluation in patients with microscopic rather than gross hematuria—both require thorough workup 2, 3, 5

Correlation with anticoagulation intensity: While vitamin K antagonist studies show correlation between INR levels and microscopic hematuria 8, apixaban's predictable pharmacokinetics mean hematuria at therapeutic doses still warrants investigation rather than dose adjustment alone 1