Which of the following factors requires warfarin rather than a direct‑acting oral anticoagulant (DOAC) for secondary stroke prevention: pregnancy, obesity (BMI 35 kg/m²), bioprosthetic mitral valve, moderate rheumatic mitral stenosis, or end‑stage renal disease?

Warfarin Requirements for Secondary Stroke Prevention

Moderate mitral stenosis and end-stage renal disease (ESRD) are the two factors that require warfarin instead of a DOAC for secondary stroke prevention. Pregnancy contraindicates all oral anticoagulants in favor of heparin-based therapy, BMI of 35 does not preclude DOAC use, and bioprosthetic mitral valves do not have sufficient evidence mandating warfarin over DOACs.

Moderate Mitral Stenosis: Absolute Indication for Warfarin

DOACs are contraindicated in patients with moderate to severe mitral stenosis, making warfarin the only acceptable oral anticoagulant option. 1, 2

• The 2021 AHA/ASA guidelines explicitly state that in patients with AF and stroke or TIA who have moderate to severe mitral stenosis or a mechanical heart valve, apixaban, dabigatran, edoxaban, or rivaroxaban are not recommended; warfarin is required instead 1
• This contraindication applies to rheumatic mitral stenosis regardless of whether the patient is in atrial fibrillation or sinus rhythm 2, 3
• The target INR for moderate to severe mitral stenosis is 2.5 (range 2.0-3.0) 2, 4
• All major DOAC trials excluded patients with moderate to severe mitral stenosis, leaving no safety or efficacy data for this population 5, 6

Common pitfall: Clinicians may mistakenly prescribe DOACs for mild mitral stenosis or mitral regurgitation. The contraindication specifically applies to moderate to severe stenosis—mitral regurgitation alone does not mandate warfarin unless it is rheumatic in origin with associated valvular changes 3

End-Stage Renal Disease: Warfarin Preferred

In patients with ESRD or on dialysis, warfarin or apixaban (dose-adjusted) may be reasonable, but warfarin remains the better-studied option. 1

• The 2021 AHA/ASA guidelines state it "may be reasonable" to use warfarin or apixaban in ESRD patients, reflecting limited evidence for DOACs in this population 1
• Most DOAC trials excluded patients with severe renal impairment (CrCl <25-30 mL/min), creating an evidence gap 1
• Warfarin does not require renal clearance and has decades of safety data in dialysis patients, making it the more conservative choice 1

Practical consideration: If apixaban is chosen for ESRD, dose adjustment is required. However, given the lack of robust trial data, warfarin with INR monitoring remains the safer default for secondary stroke prevention in dialysis patients 1

Pregnancy: Neither Warfarin Nor DOACs Are Appropriate

Pregnancy requires heparin-based anticoagulation (UFH or LMWH), not oral anticoagulants, due to teratogenic risks. 1

• Warfarin crosses the placenta and causes fetal warfarin syndrome (nasal hypoplasia, stippled epiphyses) when used in the first trimester, plus risk of fetal hemorrhage throughout pregnancy 1
• DOACs are contraindicated in pregnancy due to unknown teratogenic potential and lack of safety data 1
• For high-risk conditions requiring anticoagulation (e.g., mechanical valves, known thrombophilia), adjusted-dose UFH or LMWH throughout pregnancy is recommended 1
• In select high-risk cases, warfarin may be used from week 13 to mid-third trimester, then switched back to heparin before delivery—but this is not standard practice 1

Critical point: The question asks which factor requires warfarin "instead of a DOAC." Pregnancy does not require warfarin; it requires avoiding all oral anticoagulants in favor of parenteral therapy 1

BMI of 35: No Contraindication to DOACs

Obesity with BMI 35 does not require warfarin over DOACs.

• DOAC trials included patients across a wide BMI range, and obesity alone is not listed as a contraindication in guidelines 1
• While extreme obesity (BMI >40-50) raises theoretical concerns about DOAC pharmacokinetics, BMI 35 falls within the studied range and does not mandate warfarin 1

Bioprosthetic Mitral Valve: Insufficient Evidence to Mandate Warfarin

Bioprosthetic valves do not have a guideline-based contraindication to DOACs, though evidence is limited. 1, 6

• The 2021 AHA/ASA guidelines note that patients with bioprosthetic valves are typically managed with antiplatelet therapy, and the benefit of switching to anticoagulation (warfarin or DOAC) after stroke is unknown 1
• The RIVER trial demonstrated safety and efficacy of rivaroxaban in patients with bioprosthetic mitral valves and AF, though the indication for valve replacement (stenosis vs. regurgitation) was not specified 5
• Current guidelines do not mandate warfarin over DOACs for bioprosthetic valves, unlike the absolute contraindication for mechanical valves 1, 7, 4

Nuance: The FDA label for warfarin recommends INR 2.0-3.0 for bioprosthetic mitral valves for the first 3 months post-implantation, but this does not extend to long-term secondary stroke prevention where DOACs remain an option 4

Summary Algorithm for Choosing Warfarin Over DOACs

1. Moderate to severe mitral stenosis → Warfarin mandatory (INR 2.0-3.0) 1, 2
2. Mechanical heart valve → Warfarin mandatory (INR varies by valve type/position) 1, 7, 4
3. ESRD/dialysis → Warfarin preferred (or apixaban with caution) 1
4. Pregnancy → Neither warfarin nor DOAC; use UFH or LMWH 1
5. Bioprosthetic valve → Either warfarin or DOAC acceptable; insufficient evidence to mandate one over the other 1, 5, 6
6. Obesity (BMI 35) → DOAC acceptable 1