New Oral Anticoagulants: Implications for Health Systems

Introduction

Atrial fibrillation (AF) is the most common dysrhythmia experienced in the United States, with more than 2.2 million adults identified with AF in 2008.¹ It is expected that the prevalence of AF will increase over the next several decades as the population ages due to its high association with advanced aging and other cardiovascular disease. The major determinant of AF-related morbidity and mortality is typically not the dysrhythmia itself but rather the development of cardioembolic ischemic stroke related to blood stasis within the left atrium. This pathophysiology increases the risk of stroke in patients with AF approximately 4 to 5 times over patients without AF.¹ Given the catastrophic consequences of ischemic stroke related to AF, stroke prevention is of significant importance in the overall treatment of a patient with AF. Previously, stroke prophylaxis consisted of either the oral vitamin-K antagonist warfarin or the antiplatelet aspirin. However, the emergence of new classes of oral anticoagulants has added significant complexity to the prevention of stroke in patients with AF. Moreover, the use of these agents will add challenges for health-system pharmacy practices and may complicate existing paradigms for managing anticoagulation within these.

Efficacy and Safety of New Oral Anticoagulants

All of the major evidence-based guidelines recommend the use of anticoagulants in AF patients at high risk for stroke and that anticoagulation be at least considered for patients with intermediate risk.^2-5 Until recently, the only available oral anticoagulant for this use was warfarin, which has become the gold standard. As such, each of the new oral anticoagulants has been compared with warfarin in the prevention of stroke in AF patients.

Direct Thrombin Inhibitors

Ximelagatran was the first approved oral direct thrombin inhibitor internationally, but was rejected by the FDA and eventually withdrawn in 2006 because of hepatotoxicity risks.⁶ Dabigatran was subsequently approved by the FDA in 2011 for the prevention of stroke and systemic embolism in nonvalvular AF based on the RELY trial,⁷ which compared dabigatran with warfarin for stroke prevention in patients with AF. Overall, the 110-mg group was noninferior to warfarin in the efficacy end point of stroke or systemic embolism (annual event rate 1.53% vs 1.69%), and the 150-mg group was superior to warfarin (1.11% vs 1.69%, p <0.001). Patients treated with 110 mg had fewer major bleeding events than those treated with warfarin, whereas the 150 mg group had similar overall major bleeding rates but less intracerebral hemorrhage (ICH) and greater gastrointestinal (GI) bleeding. Warfarin management in the trial produced an overall mean time in therapeutic range (TTR) of 64%. When the mean TTR was greater than 65.5%, the risk of stroke, systemic embolism, and rates of major bleeding were the same across all groups. However, the reductions in ICH and increases in GI bleeding noted with dabigatran in the overall study were maintained.⁸ The FDA only approved the 150-mg dose because of its superiority over the 110-mg dose in the prevention of stroke or systemic embolism and additionally approved a 75-mg dose for patients with a creatinine clearance of 15 to 30 ml/min based on pharmacokinetic extrapolation.⁹ The FDA has recently added a boxed warning to the dabigatran label regarding the risk of stroke following drug discontinuation.

Factor-Xa Inhibitors

Rivaroxaban was the first oral factor Xa inhibitor to be approved by the FDA for stroke and systemic embolism prevention in patients with nonvalvular AF. The ROCKET-AF trial was the phase III study that led to the label approval of rivaroxaban for stroke prevention in AF.¹⁰ Overall, rivaroxaban was noninferior to warfarin in the prevention of stroke or systemic embolism (annual event rate 1.7% vs 2.2%) and resulted in no difference in major bleeding events. Notably, the ROCKET-AF trial enrolled higher-stroke-risk patients compared with other trials with new oral anticoagulants. Warfarin management in the trial, however, only produced an overall mean TTR of 55%, a lower rate than achieved in comparable trials of new oral anticoagulants. A significantly higher rate of stroke or systemic embolism was identified with rivaroxaban-treated patients when the study drug was discontinued, which has led to a boxed warning in the rivaroxaban product labeling that providers should consider bridging patients with alternative anticoagulation upon discontinuation.

Apixaban is the latest oral factor Xa inhibitor approved by the FDA for the prevention of stroke and systemic embolism in patients with AF secondary to the results of the ARISTOTLE trial.¹¹ Apixaban was superior to warfarin in the prevention of stroke or systemic embolism (annual event rate 1.27% vs 1.60%, p = 0.01), and it had fewer major bleeding events, including ICH. Apixaban was also compared with aspirin alone in patients with AF having moderate to high stroke risk who were deemed unsuitable for anticoagulation with vitamin K antagonists in the AVERROES trial.12 Indeed, apixaban’s clear benefit over aspirin in stroke or systemic embolism resulted in the early termination of the trial. In addition, major bleeding rates between the apixaban and aspirin groups were not significantly different, although minor bleeding was increased in patients taking apixaban.

Special Issues in Health Systems

Formulary Management

Typical formulary management practices within health systems seek to avoid duplication within therapeutic classes in order to minimize inventory costs and reduce complexity of therapy. Given the high medication safety risk with anticoagulants and the uniqueness of each therapy, this is not a recommended practice with the new oral anticoagulants at this time and strong consideration should be given to maintaining all three agents on a formulary. If streamlining available agents within therapeutic classes is pursued, this should at minimum be performed in a protocolized manner based on the pharmacology of each agent.

Dosing and Administration

Specific dosing information for each new oral anticoagulant can be found in Online Table 1. Of note, each oral anticoagulant requires adjustment in patients with varying degrees of renal dysfunction. The use of electronic health records (EHRs) and decision support tools for the identification of patients with marginal or fluctuating renal function should be a key element of the adoption of these agents into health-system formularies.

Table 1. Selected Pharmacologic Characteristics of Oral Anticoagulants

Warfarin

Dabigatran

Rivaroxaban

Apixaban

Mechanism of action

Vitamin K epoxide reductase inhibitor; decreases synthesis of factors II, VII, IX, X

Direct thrombin inhibitor

Direct factor Xa inhibitor

Direct factor Xa inhibitor

Standard dose

Variable—based on INR

150 mg twice daily

20 mg once daily with the evening meal

5 mg twice daily

Alternative dose

Variable—based on INR

CrCl 15 to 30 mL/minute:

75 mg twice daily

CrCl 15 to 50 mL/minute:

15 mg once daily with the evening meal

2.5 mg twice daily^a

Prodrug

No

Yes

No

No

Bioavailability

100%

3% to 7%

~66% without food, increased to 80% to 100% with food

~50%

P-gp Substrate

No

Yes

Yes

Yes

Hepatic elimination

Metabolized primarily by CYP2C9; lesser isoenzymes include CYP3A4, CYP2C19, CYP1A2, others

Glucuronidated to active acyl glucuronide isomers (<10% activity of parent compound)

Metabolized by CYP3A4/5 and CYP2J2; 28% eliminated in feces

Metabolized primarily by CYP3A4/5; minor contributions from other isoenzymes; ~25% eliminated in feces

Renal elimination

92% as metabolites

80% as unchanged drug

66% (36% as unchanged drug)

~27% as unchanged drug

Half-life

20 to 60 hours

12 to 17 hours

5 to 9 hours

11 to 13 hours in elderly

~12 hours

Discontinuation Interval prior to invasive procedure

5 to 7 days; monitor INR to ensure drug clearance

CrCl >50^b ml/minute: 1 to 2 days

CrCl <50^b ml/minute: 3 to 5 days

24 hours

24 hours if low-bleeding risk procedure

48 hours if high-bleeding risk procedure

Protein binding

99%

35%

92%—95%

87%

Drug-drug interactions

Numerous; moderate-strong CYP2C9 and 3A4 inhibitors; antibiotics; exogenous vitamin K

Avoid use of P-gp inducers and inhibitors; rifampin contraindicated; reduce dose to 75 mg bid if CrCL 30 to 50 ml/min with concomitant use of dronedarone or oral ketoconazole

Avoid use of strong CYP3A4 + P-gp inhibitors

Avoid use of strong CYP3A4 + P-gp inhibitors

^aPatients in ARISTOTLE and AVERROES received 2.5 mg twice daily if they had 2 or more of the following characteristics: age ≥80, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

^bConsider longer interval for patients undergoing major surgery, spinal puncture, or epidural placement

CrCl = creatinine clearance; CYP = cytochrome P450; INR = international normalized ratio; P-gp = P-glycoprotein.

Other dosing issues exist with these agents that are unique to health systems. Dabigatran may not be removed from its original bottle for repackaging; unit-dose products are available from the manufacturer for use in automated carousels or cabinets. In addition, the dabigatran capsule is a unique pharmaceutical product containing a pro-drug pellet core containing tartaric acid to enhance bioavailability. As such, the dabigatran capsule may not be opened, crushed, or manipulated in any way without an unsafe increase in bioavailability and drug exposure to the patient.¹³ Specific education and error mitigation efforts related to this potential practice should exist within health systems and ideally leverage the EHR. Patients with feeding tubes, for example, should have special precautions to ensure that dabigatran is not administered via pertube routes given the safety risks.

Rivaroxaban administration also needs to be considered for adaptation within a health system. Doses greater than 10 mg require administration with food to enhance bioavailability and therefore systems should be in place to facilitate appropriate timing with meal service. The effect of short-term fasting for procedures on the efficacy of rivaroxaban is unknown, but likely bioavailability is lessened during these periods. Rivaroxaban bioavailability is also reduced (29% decrease in AUC and 56% decrease in C_max) when gastric and proximal small intestine absorption are bypassed.¹⁴ Rivaroxaban therefore should not be administered in patients with nasojejunal feeding tubes or other anatomical variants that bypass the gastric and proximal small intestine systems.

Apixaban may be administered without regard to meals. Maintenance of an every-12-hours schedule is optimal. No specific guidance exists regarding altered absorption in patients with feeding tubes.

Procedural Management

The appropriate timing of discontinuation and reinitiation of the new oral anticoagulants with invasive procedures is particularly challenging given the lack of a standardized coagulation test which reliably predicts drug effect. The FDA has provided general recommendations regarding timing of discontinuation but these must be individualized to the patient and procedure. A summary of these recommendations is provided in Online Table 1. An institutional guideline is highly recommended in order to guide clinicians as to the appropriate general best practices. In addition, the availability of expert consultation should be provided for emergent procedures and for unique circumstances. The exact appropriate timing of new oral anticoagulants relative to procedures may provide a role for therapeutic drug monitoring of these agents in the future once these practices are defined. For post-procedure management, awareness should be heightened that these agents are more akin to parenteral anticoagulants, whereupon a therapeutic effect is evident shortly after the first dose, rather than historical practices with warfarin where therapeutic anticoagulation is slowly (re)introduced to the patient.

Conclusions

New oral anticoagulants have added significant complexity to the prevention of stroke in patients with AF. Many of these challenges are unique to health systems or other facilities. Specific error mitigation and prevention efforts may be found in Table 2. However, in many cases these new anticoagulants may increase access to anticoagulation therapy and improve outcomes due to more consistent effects compared with warfarin.

Pharmacists practicing in anticoagulation management may be particularly impacted by the adoption of these new agents. However, warfarin will continue to serve as the drug of choice in many circumstances, ensuring that many patients will continue to use these services. Additionally, the complexity of decision making and the significant number of unanswered clinical challenges provide a strong role for the pharmacist in the management of anticoagulant therapy in patients with AF.

Steven P. Dunn, PharmD, BCPS, is a pharmacy clinical coordinator, cardiology, University of Virginia Health System, Charlottesville, Virginia Hasan Kazmi, PharmD, is a PGY-1 pharmacy resident, University of Virginia Health System, Charlottesville, Virginia

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