Atrial fibrillation affects millions of patients in the United States and imparts a five-fold increase in stroke risk, as compared to the general population.¹ Oral anticoagulation is the mainstay of treatment for thromboprophylaxis in atrial fibrillation patients. Until recently, vitamin K antagonists (warfarin in the US) were the sole option for patients at moderate to high risk for stroke or systemic embolism. Now there are several novel oral anticoagulants (NOAC) available in the US as alternatives to warfarin, with good evidence for their efficacy and safety.^2-4 While dabigatran, rivaroxaban, and apixaban have been approved for use, there is little practical and even less published experience with these drugs in common clinical situations that require transitions onto or off of NOACs. We aim to discuss the risk of temporary interruptions, the possible hazard of transitioning from one anticoagulant to another, the pharmacokinetic properties of NOACs, and the data around bridging with oral anticoagulants.

There are three distinct scenarios that clinicians are challenged with in managing oral anticoagulation. The first is initiation of anticoagulation in a warfarin- or NOAC-naïve patient. The second is temporary interruption of oral anticoagulation for emergent health problems, elective procedures, or new medications and the third is transition from one oral anticoagulant to another. Each has its own challenges, and there are limited data to discuss the risks posed in each of these clinically separate situations.

Temporary interruption of anticoagulants is common and often necessary in contemporary clinical practice. In the RE-LY trial, 25% of patients underwent temporary interruption for a surgical/invasive procedure,⁵ while in the ROCKET AF trial 33% of patients underwent temporary interruption for various reasons. In the ARISTOTLE trial, 34% of patients underwent temporary interruption for invasive procedures. Temporary interruption, with or without bridging anticoagulation, may lead to an increased risk of thrombotic and bleeding events.^6,7 However, there are very little data available for outcomes for interruption of novel oral anticoagulants. With dabigatran, Healey et al. showed that periprocedural management of dabigatran could be as safe as that of warfarin with comparable risk of bleeding events (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.59 to 1.17; P=0.28).⁵ In the case of rivaroxaban, Sherwood et al, provided similar results, showing that interruptions of rivaroxaban vs. warfarin yielded similar rates of stroke/systemic embolism (HR 0.71; 95% CI 0.34-1.49, P=0.36), and major bleeding (HR 1.17, 95% CI 0.68-2.03, P=0.57).⁸ Finally, Lopes et al provided data for apixaban indicating that interruption of the anticoagulant may be unnecessary in some cases for low risk procedures, and could safely be continued.⁹ In the cases of rivaroxaban and apixaban, final full manuscripts have not yet been published.

Transitions between oral anticoagulants can be difficult, and the risk seems to differ depending on the agents involved and the direction of transition. In a subgroup analysis of the ROCKET AF trial specifically evaluating transition of oral anticoagulation at study end, Patel and colleagues found that patients who transitioned off of rivaroxaban onto warfarin had significantly higher rates of stroke and thrombotic events when compared with patients who transitioned to open-label warfarin (HR 3.72, 95% CI: 1.51 to 9.16, p = 0.0044).¹⁰ This was not specific to rivaroxaban, as data from the ARISTOTLE trial were similar. Granger et al. showed that in patients who completed study drug, those transitioning from apixaban to open-label warfarin had a significantly higher rate of stroke or systemic embolism in the first 30 days compared with those who were on warfarin (4.02%/yr vs. 0.99%/yr).¹¹ In addition, warfarin-naïve patients starting warfarin had a higher rate of stroke or systemic embolism (5.41%/year) than warfarin-experienced patients (1.41%/year). There was no difference in stroke risk in warfarin naïve or experienced patients when they started apixaban.

There are three possible mechanisms for this phenomenon. First, the increased risk was due to a period of suboptimal anticoagulation created by the relatively short half-life and quick offset of rivaroxaban and apixaban compared with the slow onset of warfarin. Mahaffey et al. explored the transition period in detail and found that 83% of the patients in the warfarin group while only 52% of rivaroxaban group had at least one therapeutic INR value (≥2) by day 30 after transition to VKA.¹² The median time to first therapeutic INR was three days in the warfarin group and 13 days in the rivaroxaban group.

Second, this short 30-day transition period may have served to unmask the significant underlying stroke risk in the high risk population studied in ROCKET AF and the moderate risk population studied in ARISTOTLE. Finally, there may be a pharmacologic mechanism of hypercoagulability that is exploited with the start of vitamin K antagonists. These drugs cause a rapid reduction in protein C and protein S levels in vivo, while Factor II and Factor X concentrations remain high due to their longer half-lives.¹³ This may contribute to a hypercoagulable state in the first 60 hours of warfarin initiation.¹⁴ There are no data showing a rebound effect exists on cessation of NOACs. Certainly the experience of these trials should inform clinicians about the risk of transition between anticoagulants and the import of clear understanding of the NOACs’ pharmacokinetics.

The differences in pharmacokinetic properties for the NOACs can make transitions challenging. The NOACs have very different pharmacokinetic profiles, but are more predictable than vitamin K antagonists. Dabigatran, a direct thrombin inhibitor, reversibly binds thrombin and achieves peak plasma concentrations two to three hours after administration. The half-life of the medication is about 12 to 17 hours. With normal renal function, plasma concentrations should decline to 25% of steady state trough levels after 24 hours and to 5 to 10% after 48 hours of stopping the drug. Rivaroxaban is a Factor Xa inhibitor that achieves peak plasma concentration after approximately three hours. The half-life is between five to nine hours, and both the presence of renal or liver disease will result in higher than expected serum drug levels. If held for 48 hours, levels of active drug in the body should fall to <1%. Apixaban similarly peaks at approximately three hours after administration and has a plasma half-life estimated at 12 hours. It is both renally and hepatically cleared and within 48 hours of cessation, drug levels will fall to <5%. While there are little data, practical guidelines from a consensus of expert opinion recommend that these drugs be held at least 24 hours before procedures imparting low bleeding risk, and at least 48 hours before high risk procedures. In the case of dabigatran, which has a longer half-life and clearance is more sensitive to renal function, patients with reduced CrCl (<80) should probably hold the drug for longer periods (72 to 96 hours) prior to procedures.¹⁵

Bridging for any oral anticoagulant is controversial. Recent guidelines from the American College of Chest Physicians indicate that they would favor no bridging therapy in low to moderate risk patients, and possible bridging therapy for moderate to high risk patients.¹⁶ However, it is unclear how these recommendations apply to the NOACs7 given the absence of such data with these new agents. Also, the most common outpatient bridging agents, enoxaparin and dalteparin, have similar pharmacokinetics to novel oral anticoagulants, begging the question of whether the novel agents themselves could be used in place of standard bridging injectable medications. Research needs to be undertaken to explore the safety of bridging with NOACs and to determine the most effective strategy for transition. The BRIDGE trial will provide data that evaluates the safety and potential efficacy of bridging therapeutic strategies for patients on chronic warfarin.¹⁷ However, patients on NOAC were excluded from enrollment. The lack of data for bridging in patients treated with NOACs serves to underscore the need for further investigation.

Clinicians face new choices and challenges with the introduction of NOACs into practice. A few points are clear, first clinicians should avoid interruption of oral anticoagulation if at all possible, second that pharmacokinetic principles should be considered if NOACs must be stopped and initiated, and finally more research is needed to answer questions on interruption and bridging therapy.

References

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2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151.
3. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
4. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.
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11. Granger C.B. AJH, Hanna M., Wang J., Mohan P., Lawrence J., Hylek E., Ansell J.E. and Wallentin L. Events after discontinuation of randomized treatment at the end of the ARISTOTLE trial. Eur Heart J 2012;33(suppl 1):685-686.
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13. Stirling Y. Warfarin-induced changes in procoagulant and anticoagulant proteins. Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 1995;6:361-373.
14. Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997;126:133-136.
15. Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651.
16. Guyatt GH, Akl EA, Crowther M, Schunemann HJ, Gutterman DD, Zelman Lewis S. Introduction to the ninth edition: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):48S-52S.
17. Investigators TBS. Bridging Anticoagulation: Is it Needed When Warfarin Is Interrupted Around the Time of a Surgery or Procedure? Circulation 2012 2012;125(12):e496-e498.

Keywords: Anticoagulants, Atrial Fibrillation, Benzimidazoles, Cytarabine, Embolism, Morpholines, Pyrazoles, Pyridones, Stroke, Thiophenes, Vitamin K, Warfarin, beta-Alanine

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