Breakthrough Systemic Embolism on Therapeutic Anticoagulation in Atrial Fibrillation: Warfarin vs. DOAC (Apixaban), Management, and Precautions

By: Dr. Abdelwahab Arrazaghi, MD, FABIM, FRCPC

Abstract

Two patients with atrial fibrillation (AF) experienced systemic embolism despite guideline-concordant oral anticoagulation (OAC): (1) splenic infarction on therapeutic warfarin (INR >2) and (2) renal infarction on apixaban 5 mg twice daily. These rare but recognized “breakthrough” events occur with both vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). This review compares failure rates of warfarin vs. DOACs, explores underlying mechanisms, outlines a practical evaluation, and provides evidence-based management strategies—including when to consider left atrial appendage occlusion (LAAO).

Case Vignettes

Case A (Warfarin): AF on warfarin with therapeutic INR >2 presented with acute left upper-quadrant pain; CT confirmed splenic infarction.

Case B (Apixaban): AF on apixaban 5 mg twice daily with appropriate dosing criteria presented with flank pain; CT confirmed renal infarction.

These cases highlight the residual risk of systemic embolism despite appropriate anticoagulation.

How Often Does Anticoagulation Fail?

• Apixaban vs. warfarin (ARISTOTLE trial): stroke/systemic embolism (SE) occurred at 1.27%/year with apixaban vs. 1.60%/year with warfarin—with apixaban showing both efficacy and safety benefits.

• Residual risk perspective: contemporary data suggest ~1–2%/year breakthrough ischemic events in anticoagulated AF patients, depending on baseline risk.

• Warfarin: Outcomes strongly depend on time in therapeutic range (TTR). TTR <65% markedly increases stroke/SE, bleeding, and mortality; optimal control requires TTR ≥70–75%. A single therapeutic INR may mask poor historical control.

• DOACs: Failures often relate to missed doses, drug interactions, underdosing, renal dysfunction, or extremes of body size.

  
  

Why Do Thromboembolic Events Occur on OAC?

Contributors include:

• Suboptimal exposure

  • Warfarin: low TTR, vitamin K variability, drug interactions.

  • DOACs: missed doses; CYP3A4/P-gp inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort); renal impairment; extreme body weight; malabsorption.

• Thrombus despite OAC

  • Left atrial appendage (LAA) thrombus occurs in ~2–4% of AF patients even on therapeutic OAC; higher risk with persistent AF, left atrial dilation, low LAA velocity, and heart failure.

• Alternative embolic sources / prothrombotic states

  • Aortic/arterial plaque, endocarditis, malignancy, myeloproliferative disorders, paradoxical embolism, or antiphospholipid syndrome (APS).

  • DOACs are not recommended in high-risk APS; warfarin is preferred.

    
    

Practical Evaluation After Breakthrough Embolism

Step 1 — Confirm exposure & interactions

• Verify adherence (pharmacy records, pill counts).

• Review drug–drug/supplement interactions.

• Reassess renal function, body weight, and correct DOAC dosing.

• For warfarin: calculate TTR over prior 6–12 months.

Step 2 — Consider drug-level testing (selective use)

• DOAC-specific anti–factor Xa assays may clarify exposure in special cases (malabsorption, extreme weight, renal failure).

Step 3 — Search for embolic substrate

• Echocardiography (TEE/cardiac CT) for LAA thrombus, LA size, LV function, valves.

• Vascular imaging (aorta, renal/splenic arteries).

• Targeted hypercoagulable work-up if suspicion (APS, JAK2 mutation, occult malignancy).

Step 4 — Reassess stroke & bleeding risk

• Update CHA₂DS₂-VASc and HAS-BLED scores.

• Optimize modifiable risk factors (BP, sleep apnea, weight, alcohol, diabetes).

  
  

Condition-Specific Management

A) Splenic Infarction (on warfarin)

• Supportive care: hydration, analgesia, infection management.

• Continue anticoagulation unless bleeding/rupture.

• Monitor for complications (abscess, rupture).

• Vaccinate if functional asplenia suspected.

B) Renal Infarction (on apixaban)

• Confirm with CT/CTA.

• Continue anticoagulation; parenteral therapy optional if diagnostic uncertainty.

• Endovascular therapy only in proximal occlusion, early presentation, or solitary kidney.

• Monitor kidney function: AKI occurs in 20–40%, chronic impairment in ~⅓.

  
  

What to Change in Anticoagulation After a Breakthrough Event?

• On warfarin:

  • If TTR <70%, switch to a DOAC or intensify warfarin management.

  • If TTR ≥70–75% but event occurs, consider switching to a DOAC (apixaban preferred).

• On apixaban/DOAC:

  • Correct reversible contributors (adherence, interactions, renal dosing).

  • If exposure verified, consider switching class (e.g., to dabigatran) or to warfarin (INR 2–3).

  • Adding antiplatelet therapy is not recommended without another clear indication.

• If LAA thrombus persists despite OAC:

  • Continue therapy and re-image.

  • If unresolved, multidisciplinary discussion for LAAO.

    
    

Left Atrial Appendage Occlusion (LAAO)

• 2023 ACC/AHA/ACCP/HRS AF Guideline:

  • Reasonable (Class 2a) if CHA₂DS₂-VASc ≥2 and contraindication to OAC.

  • May be reasonable (Class 2b) for recurrent embolism despite adequate OAC.

    
    

Key Precautions & Prevention Checklist

• Confirm correct DOAC dosing (apixaban 5 mg bid unless ≥2 of: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL).

• Eliminate drug interactions.

• Ensure adherence (pillbox, reminders, pharmacy packs).

• Monitor renal function at least annually.

• Warfarin: maintain TTR ≥70%.

• Cardiac imaging for LAA thrombus after breakthrough event.

• Evaluate APS/other thrombophilias when appropriate.

• Optimize AF and vascular risk factors.

  
  

Key Take-Home Points

• Both warfarin and DOACs leave a residual 1–2%/yr risk of stroke/systemic embolism.

• Breakthrough events require a structured evaluation: exposure, interactions, renal function, imaging, targeted labs.

• Do not routinely add antiplatelet therapy to OAC in AF without another indication.

• Switching agents or considering LAAO may be appropriate in selected patients.

  
  

References

• Granger CB, et al. N Engl J Med. 2011 (ARISTOTLE trial).

• Paciaroni M, et al. Int J Stroke. 2021.

• StatPearls: Splenic Infarcts. Updated 2024.

• StatPearls: Renal Infarction. Updated 2025.

• 2023 ACC/AHA/ACCP/HRS Guideline for AF. Circulation. 2023.

• Gorczyca I, et al. JACC. 2021.

• Ren JF, et al. World J Cardiol. 2018; Sci Rep. 2022.

• Pengo V, et al. APS & anticoagulation guidance. ASH/ISTH/EULAR.