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A Review of New Oral Anticoagulants: Some 'Factors' to Consider


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Jennifer Day, PharmD, BCPS
Baptist Health Transplant Institute
Heart Transplant and Mechanical Circulatory Support Program
Little Rock, AR, USA
email




An increasing number of patients are being treated with the novel oral anticoagulants (NOACs), in lieu of the vitamin K antagonist, warfarin, for a variety of indications. Although quite promising in some aspects (predictable effect without need for monitoring, fewer food and drug interactions, shorter plasma half-life, and improved efficacy/safety ratio), these drugs present a new set of challenges (no reversal agent, lack of evidence in patients with valves/devices, dependence on strict compliance with dosing), which require careful consideration in the already tenuous course of transplant and VAD patient populations.

Dabigatran (Pradaxa®), an oral direct thrombin inhibitor (DTI), was the first of its like to come to market. Approved in the U.S. for use in the prevention of stroke and systemic embolism in patients with non-valvular A fib, it is also approved for primary venous thromboembolism (VTE) prevention in patients undergoing elective total hip and knee replacements in Europe and Canada. Use is not recommended in patients with mechanical or bioprosthetic heart valves [1]. Dose adjustments must be made in patients with moderate renal impairment (CrCl 15-30 ml/min), and use should be avoided in renal failure (CrCl < 15 ml/min) [1-3]. Notable effects on dabigatran exposure are seen with concurrent therapy of inducers or inhibitors (i.e. cyclosporines) of the P-glycoprotein (P-gp) system, which may require dose adjustment or discontinuation [4] (see Table 1 for a summary of indications, dosing, and drug interactions).

Another special consideration with dabigatran is the significantly increased rate of gastrointestinal adverse reactions (bleeding and gastritis-like symptoms) compared to warfarin [1,4]. These GI effects present a significant concern in patients already at risk for GI bleeding due to pulsatile ventricular assist devices or chronic steroid use post transplantation. However, the lack of routine monitoring and first dose effectiveness make dabigatran a desirable option for anticoagulation in certain patient populations.

Two other oral anticoagulants have since emerged, the factor Xa inhibitors, Rivaroxaban (Xarelto®) and Apixaban (Eliquis®). Like dabigatran, the proposed advantages to these agents include the lack of routine monitoring and their first dose effectiveness, eliminating the need for bridging with injectable anticoagulants. In the United States, rivaroxaban carries an additional indication for use in the treatment of deep vein thrombosis, pulmonary embolism, and/or secondary prophylaxis of VTE. The bioavailability of rivaroxaban is significantly increased when taken with food, so it should be dosed with a meal [6]. Both Xa inhibitors are labeled with black box warnings for the increased risk of thrombotic events after discontinuation in the absence of adequate alternative anticoagulation [6,7]. Since the anticoagulant effect fades rapidly 12 - 24 hours after the last intake, these agents may not provide adequate protection for patients with non-compliance to medication regimens [1, 5-7]. Avoidance or reduced dosing for both rivaroxaban and apixaban are recommended with co-administration of CYP3A4 and P-gp inducers and inhibitors [6,7]. Like dabigatran, no direct reversal agent is available.

Because there is no reversal for the anticoagulant effect of NOACs, yet also an increased risk of thrombosis if discontinued abruptly in the absence of alternative anticoagulation, careful consideration must be given to their use in the peri-operative and interventional setting. Table 2 highlights the recommendations for discontinuing these DTI and factor Xa inhibitors prior to surgery and other procedures. In emergent situations, anticoagulation assays may provide a qualitative assessment of the presence of dabigatran (aPTT) or factor Xa inhibitors (PT). In these cases, the time delay between last intake and blood sampling must be carefully considered. For instance, in patients treated with dabigatran, an aPTT exceeding two times the upper limit of normal at trough (12 - 24 hours after ingestion) may indicate a higher risk for bleeding [5]. At this time, however, there is insufficient data and no specific recommendations to guide the use and interpretation of these tests in DTI or Xa inhibitor therapy. Table 3 summarizes recommendations for the safe conversion of NOACs to or from warfarin.

In summary, we must be diligent as we evaluate new patients and plan surgical and other procedures to be aware of the potential use of NOACs. We must minimize the potential increased risk for both bleeding and thrombosis by ensuring the DTI or factor Xa inhibitors are properly dosed and discontinued around procedures. More data is needed to evaluate the safety and efficacy of using these agents in patients with mechanical valves and devices, as well. Given the relatively narrow patient population studied in clinical trials with these agents to date and the lack of predictable reversal or remedy in case of hemorrhage, we probably aren't ready for NOACs to replace our old friend, warfarin, in the care of our patients implanted with LVADs just yet. We must continue to consider all the 'factors' when choosing anticoagulants for all our patients.

Table 1

Drug Name

Dabigatran
(Pradaxa®)

Rivaroxaban
(Xarelto®)

Apixaban
(Eliquis®)

Drug Class

Direct Thrombin Inhibitor

Factor Xa Inhibitor

Factor Xa Inhibitor

Prophylaxis of stroke and systemic embolism in non-valvular Atrial Fib

US Labeling:
• 150 mg BID
• CrCl 30-50 ml/min or with dronedarone/ ketoconazole: 75 mg BID
• CrCl 15-30 ml/min: 75 g BID
• CrCl <15 ml/min: not recommended
Canadian Labeling:
• CrCl >30 ml/min and age < 75: 150 mg BID
• Age > 80: 110 mg BID• CrCl < 30: not recommended

• 20 mg daily (with food)
• CrCl 15-50 ml/min: 15 mg daily
• CrCl <15 ml/min: not recommended

• 5 mg BID
• With any 2/3 of the following: age≥80 weight ≤60kg serum Cr≥1.5: 2.5 mg BID
• With azoles, erythromycins, or strong dual inhibitors of CYP3A4/P-gp: 2.5 mg BID

Treatment of DVT, PE, and to decrease risk for recurrent VTE

Not currently approved

• 15 mg BID x 3 weeks followed by 20 mg daily (with food)

Not currently approved

Peak Effect

1 hour (delayed 2 hours by food)

2 - 4 hours

3-4 hours

Half-life (t1/2)

12-17 hours
Elderly: 14-17 hours
Mild/mod renal impairment: 15-18 hours
Severe renal impairment: 28 hours

5-9 hours
Elderly: 11-13 hours

12 hours

Drug Interactions/ Metabolism

P-glycoproteins

CYP3A4, CYP3A5, CYP2J2

CYP3A4 and P-glycoproteins



Table 2 - Discontinuation interval prior to invasive procedures

Dabigatran

Rivaroxaban

Apixaban

CrCl > 50 ml/min:
24 to 48 hours

CrCl < 50 ml/min:
72 to 120 hours
(3 - 5 days)*

24 hours

24 hours for low-bleeding risk procedure or where bleeding would be non-critical and easily controlled

48 hours if high-bleeding risk procedure

*Consider longer interval for patients undergoing major surgery, spinal puncture, epidural placement, or if complete hemostasis may be required.



Table 3 - Converting to/from warfarin

 

Dabigatran

Rivaroxaban

Apixaban

Warfarin to new agent

• Stop warfarin
• Once INR <2 begin Dabigatran

• Stop warfarin
• Once INR <3 begin rivaroxaban

• Stop warfarin
• Once INR <2 begin apixaban

New agent to Warfarin

• CrCl≥50 ml/min, start warfarin 3 days before stopping dabigatran
• CrCl 30-50ml/min, start warfarin 2 days before stopping dabigatran
• CrCl 15-30ml/min, start warfarin 1 day before stopping dabigatran
• CrCl ≤15ml/min, no recommendations can be made

• Stop rivaroxaban
• Begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been due
• Stop parenteral anticoagulant when INR is acceptable

• Stop apixaban
• Begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been due
• Stop pareneteral anticoagulant when INR is acceptable



Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Pradaxa® (dabigatran) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2013 April.
  2. Dunn, Steven P., Kazmi, Hasan. "New Oral Anticoagulants: Implications for Health Systems." Pharmacy Times Health System Edition; 2013 July 22.
  3. Press Release "European Medicines Agency Updates on Safety of Pradaxa." EMA/CHMP/903767/2011; 2011 Nov 18.
  4. Ejendal, KHC, Hrycyne, CA. "Differential Sensitivities of the Human ATP-binding Cassette Transporters ABCG2 and P-glycoprotein to Cyclosporin A." Molecular Pharmacology. 2005; 67:902-11.
  5. Heidbuchel, Hein, Verhamme, Peter, Alings, Marco, et al. "EHRA Practical Guide on the Use of New Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation: Executive Summary." European Heart Journal. 2013; 10:1093-1123.
  6. Xarelto® (rivaroxaban) package insert. Titusville, NJ. Janssen Pharmaceuticals Inc., 2013 August.
  7. Eliquis® (abixaban) package insert. Princeton, NJ. Bristol-Myers Squibb Company; 2012 December.



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