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Dr. Wassim Shaheen–Is It Time To Say “Goodbye Warfarin”?


Wassim Shaheen, MD

Vitamin K antagonist, warfarin, has been the main oral anticoagulant until recently. It is indicated for the prevention and treatment of venous thrombosis as well as thromboembolic complications associated with several conditions as atrial fibrillation, deep vein thrombosis, pulmonary embolism and metallic valves. Initiation of warfarin therapy is challenging, given the poor prediction of its pharmacodynamic response. Also different indications require different INR targets. This is summarized in table one.

Table 1

Indication INR
Treatment of DVT and PE 2-3
Pophylaxis for DVT ( high risk surgery) 2-3
Prevention of systemic embolism:Tissue valveAtrial fibrillation


Bileafletmechanicl aortic valve 2-3
Metallic mitral valve 2.5-3.5
Mechanical aortic valve ( high risk) 2.5-3.5
Recurrent systemic embolism 2.5-3.5


Furthermore, INR may become supra therapeutic and hence necessitates the administration of vitamin k, PCC and sometimes FFP. Management summary is shown in table two.

Table 2

INR Clinical scenario Management
3.1-5 No bleeding Adjust warafrin dose
5.1-9 No bleeding Adjust warafin dose
5.1-9 No bleedingNeed reversal for surgery Vitamin k 2-4 mg orally
9.1-20 No bleeding Vitamin k3-5 mg orally
9.1-20 No bleedingNeed reversal for surgery Vitamin k 10 mg IVFFP or PCC
9.1-20 Bleeding Vitamin k 10 mg IVFFP or PCC
>20 Vitamin KFFP or PCC


Recently novel anticoagulants (NOAC) have been approved by FDA as a substitute to warfarin. These are Pradaxa, Xarelto and Eliquis. All are approved for prevention of thrombosis and systemic embolization in the following conditions:

  1. Non-valvular atrial fibrillation
  2. Prevention of DVT and PE in high risk surgeries ( i.e. hip and knee surgery)
  3. Treatment of DVT and PE


None of these agents have been approved for prevention of thrombosis in metallic valves and hence should not be considered irrespective of the situation. Also when we review the data, please do remember that none of these agents were studied “ head to head” but rather they were compared to warfarin in double blinded trials.


The following tables summarize the main studies that lead to FDA approval of these three agents in non valvular atrial fibrillation patients.


      I. Oral anticoagulants:

Warfarin Pradaxa(Dabigtran) Xarelto( Rivaroxaban) Eliquis( Apixaban)
Mechanism Direct thrombin inhibitor Direct factor X inhibitor Direct factor X inhibitor
Bioavailability  6.5%(PH sensitive, prodrug) >80% >50%
Plasma Half life 12-14 hr 9-13 hr 8-15 hr
Renal elimination 85% 33% 27%
Protein binding 35% 95% 87%
Dialysability Yes unlikely unlikely
Dosage 150 mg BIDor75 mg BID 20 mg dailyor15 mg daily 5 mg bidor2.5 mg BID
Antidote Vitamin KFFP None None None


      II. Main Trials: 

Warfarin Pradaxa Xarelto Eliquis
Patient number 18,113 14,264 18,201
Median follow up 2 yr 1.9 yr 1.8 yr
Dose 110 & 150 mg BID 20 mg QD 5 mg BID
Renal adjustment None 15 mg QD 2.5 mg BID
CHADS score 2.2 3.5 2.1


      III. Outcome: 

  warfarin Pradaxa Xarelto Eliquis
Primary outcome RRR 35%* 21%* 21%*
Hem. Stroke RRR 74%* 41%* 49%*
Ischemic stroke RRR 24%* 6% 8%
CV death RRR 15%* 11% 11%
All death RRR 12% 15% 11%*
MI RRR INCREASED 27% 19% 12%


      IV. Bleeding:

Warfarin Pradaxa Xarelto Eliquis
Major bleeding RRR 7% Increase 4% 31% *
ICH RRR 59%* 33%* 58%*
GI bleeding RRR Increase 48% Increase 46% 11%
All bleeding RRR 9%* Increase 3% 32%*


These trials show that these agents are equivalent if not superior to warfarin in prevention of stroke in patients with non valvular atrial fibrillation. However Pradaxa has increased risk of bleeding especially in those who are older than 75 years. Also the Re-LY trial showed slight increase risk of MI. On the other hand Xarelto, though has increased risk of bleeding, it is once a day dose and may improve compliance. Eliquis has probably the least risk of bleeding compared to warfarin and the only one that showed reduced mortality. So keep in mind that these agents need to be withheld prior to any elective surgery. This final two tables summarize the time needed to hold medication prior to surgery and dosage of these agents based on patient’s clinical scenario.


      V. Dosage:

Medication Disease Dosage
Pradaxa Non Valvular atrial fibrillation 150 mg BID unless CrCl 15-30 ml/min then 75 mg/dl.Contraindicated if CrCl< 15 ml/min
Pradaxa DVT/PE prophylaxis 150 mg BID unless CrCl less 30 ml/min then no dose recommendation is available.
Pradaxa DVT/PE treatment 150 mg BID unless CrCl less 30 ml/min then no dose recommendation is available.
Xarelto Non Valvulara atrial fibrillation 20 mg once a day unless CrCl 15-50 ml/min then 15 mg once day ( Preferably with evening meal)
Xarelto DVT/PE prophylaxis 10 mg one a day ( 12 days for knee and 35 days for hip)
Xarelto DVT/PE treatment 15 mg BID for 21 days then 20 mg once a day
Eliquis Non Valvular atrial fibrillation 5mg BID unless 2/3 met then 2.5 mg BID( age >80 yr, wt<60 kg or r >1.5)
Eliquis DVT/PE prophylaxis 2.5mg BID ( 12 days for knee and 35 days for hip)
Eliquis DVT/PE treatment 10 mg bid for 1 week then 5 mg BID


*Be aware of mediation interaction with these agents that affect dosage administration


      VI. Time to hold NOAC prior to elective surgery:

Medication Duration held
Pradaxa 1-2 days if CrCl>50 ml/min3-5 days if CrCCl 15-50 ml/min
Xarelto At least 1 day
Eliquis 24 hours f low risk surgery for bleeding48 hours if high risk surgery for bleeding



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