What are the contraindications for Direct Oral Anticoagulants (DOACs)?

Contraindications for Direct Oral Anticoagulants (DOACs)

DOACs are contraindicated in patients with mechanical heart valves, severe renal or hepatic impairment, and when taking certain medications that significantly interact with their metabolism. 1, 2

Absolute Contraindications

• Mechanical heart valves: All DOACs are contraindicated in patients with mechanical prosthetic heart valves due to increased risk of thromboembolism and bleeding 3, 2
• Pregnancy or breastfeeding: DOACs should not be used during pregnancy or while breastfeeding 1
• Severe renal impairment:
  • Apixaban: CrCl <30 mL/min 1
  • Dabigatran, edoxaban, rivaroxaban: CrCl <30 mL/min 1, 4
• Significant liver disease:
  • Child-Pugh Class B or C cirrhosis 1
  • ALT/AST >3x upper limit of normal (ULN) 1
  • Total bilirubin >2x ULN 1
  • Active hepatitis 1
• Triple-positive antiphospholipid syndrome: DOACs are not recommended for patients who are positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies due to increased thrombotic risk compared to vitamin K antagonists 5, 3

Drug Interaction Contraindications

• Strong dual inhibitors of CYP3A4 and P-glycoprotein (P-gp):
  • For rivaroxaban and apixaban: azole antifungals (ketoconazole, itraconazole), HIV protease inhibitors 1
  • For dabigatran: cyclosporine, itraconazole, ketoconazole, tacrolimus 1
• Strong inducers of P-gp: rifampin, St. John's wort (reduces DOAC efficacy) 1
• Concomitant use of other anticoagulants 1

Relative Contraindications (Use with Caution)

• Moderate renal impairment:
  • Requires dose adjustments for all DOACs 1, 6
  • Particularly important for dabigatran (80% renal elimination) 1, 4
  • Monitoring renal function is essential, especially in patients receiving nephrotoxic chemotherapy 1
• Gastrointestinal or genitourinary tract lesions: DOACs have been associated with increased risk of GI and genitourinary bleeding 1, 7
• Concomitant use of antiplatelet agents: Increases bleeding risk 1
• Unresected mucosal tumors or active mucosal lesions: Higher risk of bleeding with DOACs than with LMWH 1
• Cancer patients: Particular caution in patients with GI or genitourinary malignancies 1
• Drug-drug interactions:
  • Verapamil and diltiazem (moderate P-gp inhibitors) increase bleeding risk with dabigatran even in patients with normal kidney function 8
  • Clarithromycin and erythromycin may increase rivaroxaban levels 1
  • Antiepileptic drugs (phenytoin, carbamazepine, phenobarbital) may reduce DOAC efficacy 1
• Advanced age with multiple comorbidities: Elderly patients with multiple comorbidities require careful assessment 1, 6

DOAC-Specific Considerations

Dabigatran

• Highest renal elimination (80%) - most affected by renal impairment 1, 4
• Reduce dose to 75mg twice daily when used with dronedarone or systemic ketoconazole in patients with moderate renal impairment 3

Rivaroxaban

• Avoid in patients with CrCl <15 mL/min and those on dialysis 5
• Higher risk of drug interactions due to CYP3A4 metabolism 1

Apixaban

• Relatively safer in renal impairment but still contraindicated in severe renal dysfunction 1, 6
• Dose adjustment needed based on age, weight, and serum creatinine 1

Edoxaban

• Fewer drug-drug interactions compared to other DOACs 1
• Still contraindicated in severe renal impairment 1

Special Populations

• Cancer patients: LMWHs are preferred over DOACs in settings with increased risk of bleeding 1
• Heart failure patients: DOACs (particularly apixaban and dabigatran) are associated with less bleeding than warfarin, but require close monitoring of renal function 7
• Patients requiring urgent procedures: Consider reversal agents availability 1

Monitoring Considerations

• Regular assessment of renal function is essential, especially in patients at risk of fluctuating renal function 1, 7
• A >20% decline in renal function may necessitate DOAC dose adjustment to prevent bleeding complications 7
• Patients receiving nephrotoxic or hepatotoxic medications should be monitored more closely 1

Remember that contraindications may change as new evidence emerges, and clinical judgment is required when weighing the risks and benefits of anticoagulation in individual patients.