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

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 Valvulardisease	2-3
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
Trial		RE-LY	ROCKET AF	ARISTOTLE
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
Trial		RE-LY	ROCKET AF	ARISTOTLE
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
Trial		RE-LY	ROCKET AF	ARISTOTLE
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