New Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and its prevalence is expected to increase significantly over the next few decades.¹ Currently, it is estimated that between 2.1 and 5.1 million people are affected by AF in the United States.^2,3 As the population ages, this number is expected to increase to approximately 16 million people by 2050.³

Thromboembolic stroke is the most serious potential consequence of AF, and patients with AF face 5-fold higher risk of stroke than those without AF.³ Identification of discrete risk factors for stroke has enabled the development of risk stratification scoring systems to estimate the composite risk of stroke in patients with AF. The most widely used risk stratification system is the CHADS₂ score. This systems assigns points based on various risk factors (ie, Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and prior history of Stroke or transient ischemic attack [TIA]), and uses the composite score to stratify patients into groups at low, moderate, or high risk of stroke.⁴ The most recent evidence-based guidelines established by the American College of Cardiology Foundation/American Heart Association/ European Society of Cardiology (ACCF/AHA/ESC) as well as the guidelines of the American College of Chest Physicians (ACCP) suggest oral anticoagulation therapy rather than no therapy (level of evidence: grade 1B) for patients with AF at moderate risk of stroke (CHADS2 = 1).^5,6

Because stroke is the leading cause of serious long-term disability and the third-leading cause of death in the United States, effective strategies for stroke prophylaxis in patients with AF have a significant clinical and economic impact.⁷

BENEFITS AND LIMITATIONS OF TRADITIONAL ANTICOAGULANTS

The current standard of care recommended by ACCF/AHA/ESC is anticoagulant therapy with warfarin, a vitamin K antagonist (VKA), or antiplatelet therapy when anticoagulation is contraindicated or inappropriate.⁵ However, many patients with AF are never prescribed warfarin, and those who are may use it suboptimally, placing them at high risk of thromboembolic stroke.8 In addition, warfarin has several limitations, which makes its use difficult outside the clinical trial setting.^9,10

The pharmacodynamic effects of warfarin are influenced by diet, concomitant medications, comorbid conditions, and genetics, making treatment individualization and long-term monitoring mandatory. Dosing to maintain a therapeutic range is adjusted according to a patient’s international normalized ratio (INR), which is measured at regular intervals. The potential consequences of excessive anticoagulation (bleeding) or insufficient anticoagulation (stroke) can be catastrophic, so frequent monitoring is recommended during lifelong warfarin treatment.⁸ The recently revised ACCP guidelines recommend quarterly visitations for those with very stable INRs.⁶

The percentage of time within a therapeutic INR range (TTR) is directly related to the risk of mortality in patients with AF, with the lowest risk seen in patients who have more than 70% of their INR levels within the therapeutic range.¹¹ Unfortunately, the real-world INR levels seen in typical outpatient and community care settings are generally lower than those in patients enrolled in specialized anticoagulation clinics.^12,13 However, results of numerous studies comparing patient TTRs before and after switching from a usual care setting to specialized anticoagulation clinics have reported nominal improvements in TTR levels.^14-17 Moreover, the improved TTR levels observed after switching to an anticoagulation clinic were all below 70% and were associated with improved patient outcomes, suggesting that the benefits associated with a TTR of more than 70% might be more apparent than real. Even in an ideal anticoagulation setting, factors such as patient compliance, patient knowledge of and familiarity with correct warfarin use, and drug discontinuation inevitably play a role in variable and suboptimal INR control.^12,18,19

The limitations of warfarin have prompted extensive research to develop alternative anticoagulants that are at least as effective, but are safer and easier to use. Recently approved oral anticoagulants may provide simpler, more effective, and safer stroke prevention compared with VKAs in patients with AF. Consequently, the use of these agents as an alternative to VKAs may improve patient adherence, improve outcomes, and decrease overall healthcare costs. In 2010 and 2011, 2 new oral anticoagulants were approved by the US Food and Drug Administration (FDA) for prevention of stroke and systemic embolism in patients with nonvalvular AF. These new drugs include the direct thrombin inhibitor (DTI) dabigatran etexilate (approved October 2010) and the Factor Xa (FXa) inhibitor rivaroxaban (approved October 2011).^20,21 In addition, the FXa inhibitor apixaban is currently being considered for an AF-indication approval and has already been approved in the European Union for prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery.²² Although dabigatran is currently recommended as an alternative, the majority of patients with AF continue to be treated with warfarin.²³ This review examines the pharmacologic and clinical benefits of the new anticoagulants in the prevention of stroke and systemic embolism in patients with AF, focusing on major phase III study results.

STUDY IDENTIFICATION

A literature search was conducted of all PubMed indexed articles from January 2009 to October 2011 to identify randomized clinical studies sufficiently powered to identify rates of stroke and non—central nervous systemsystemic embolism. Subgroup analyses were excluded. A total of 12 publications were identified using the aforementioned search terms and limitations. All studies were screened for inclusion. Of these, 4 large randomized studies were identified. A search on www.clinicaltrials.gov was performed to identify additional studies. Data inclusion was based on study quality, not publication date. All searches were performed in January 2011 and updated in October 2011.

NOVEL ANTICOAGULANTS: COMPARATIVE PHARMACOLOGY

The new oral anticoagulants function by inhibiting the coagulation pathway via direct inhibition of thrombin (dabigatran) or selective site-specific inhibition of Factor Xa (rivaroxaban and apixaban).¹⁰ In contrast, warfarin modulates the formation of thrombin at multiple points in the coagulation cascade by inhibiting the recycling of vitamin K from its oxidized, inactive state to its reduced, active form. This process is necessary for the biologic activity of Factors II (prothrombin), VII, IX, and X, as well as proteins C and S.²⁴ Unlike warfarin, by specifically targeting a single coagulation factor, DTIs and FXa inhibitors do not have broad effects on multiple coagulation factors that may predispose to adverse events.²⁵

Table 1

summarizes the pharmacologic profiles of these agents.^26-28

Dabigatran

Dabigatran etexilate was the first oral anticoagulant to be approved in the United States for stroke prevention in AF.²¹ Dabigatran has an oral bioavailability of approximately 3% to 7%. It is administered as a prodrug, dabigatran etexilate, which does not exhibit any pharmacologic activity. Dabigatran etexilate is a substrate of the efflux transporter P-glycoprotein (P-gp). After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalyzed hydrolysis in plasma and in the liver. This process occurs independently of cytochrome P (CYP) 450 isozymes, but concomitant use of potent P-gp inducers (eg, rifampin) should be avoided.²¹ Originally, dose adjustments were not required when dabigatran was combined with P-gp inhibitors; however, because of postmarketing experience reports, dose adjustments (75 mg twice daily) are recommended when dabigatran is combined with potent P-gp inhibitors (ketoconazole, dronedarone) in patients with reduced renal function (creatinine clearance [CrCl] 15-30 mL/min). Dabigatran is also subject to conjugation, forming pharmacologically active acylglucuronides. Four isomers of dabigatran glucuronide exist, each accounting for less than 10% of total plasma dabigatran. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. In its active form, dabigatran has a half-life of approximately 12 to 17 hours. Approximately 80% of dabigatran is excreted via the kidneys as unchanged drug. The safety of dabigatran in patients with severe hepatic impairment has not been established, but after administration to patients with a Child-Pugh score of B, no consistent changes in exposure or pharmacodynamic were observed.²¹

Approval of dabigatran in the United States was based on the results of the phase III RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study.²⁹ The ACCP guidelines recommend 150 mg twice daily of dabigatran rather than dose-adjusted VKA therapy for patients with AF and paroxysmal AF when anticoagulation therapy is advised (grade 2B).⁶ The ACCF/AHA Task Force update on practice guidelines also recommends dabigatran as an alternative to warfarin in patients with AF (class I, level B), but indicates that switching patients already on warfarin with excellent INR control is of little value.²³

In the RE-LY study, 2 dosages of dabigatran—110 mg twice daily and 150 mg twice daily—were compared with dose-adjusted warfarin (INR 2.0-3.0) in more than 18,000 patients with AF over a median of 2 years.²⁹ The comparison between dabigatran doses was double blind, whereas warfarin was administered in an open-label fashion. The primary end point was stroke or systemic embolism. The primary safety outcome was major bleeding events. The primary analysis was designed to test whether either dose of dabigatran was noninferior to warfarin in reducing the primary end point of stroke or systemic embolism. If noninferiority was established, the agents were compared for statistical superiority.²⁹

Patient eligibility for RE-LY included electrocardiographically documented AF with at least 1 additional risk factor for stroke (eg, previous stroke, TIA, left ventricular ejection fraction less than 40%, heart failure symptoms of New York Heart Association class II or higher in the preceding 6 months, and age >75 years or age 65 to 74 years with diabetes, hypertension, or coronary artery disease).²⁹ The mean age of all patients was 71 years; 63.6% were male, and 20% had experienced a previous stroke or TIA. When stroke risk was stratified by CHADS2 score, 32% of patients had a score of 0 to 1 (low risk), 36% had a score of 2 (moderate risk), and 32% had a score of 3 to 6 (high risk). Half of enrolled patients (50%) had not previously been treated with warfarin.²⁹

Compared with warfarin, both dabigatran doses were noninferior (P <.001 for noninferiority) for the primary end point of stroke or systemic embolism, and dabigatran 150 mg was superior (P <.001) (

Figure 1

).²⁹ These findings represented a 35% reduction in risk of stroke or systemic embolism with dabigatran 150 mg twice daily versus warfarin (relative risk [RR] 0.65; 95% confidence interval [CI] 0.52-0.81). In addition, both doses of dabigatran significantly reduced the risk of hemorrhagic stroke compared with warfarin (P <.001), and dabigatran 150 mg twice daily reduced the risk of any stroke (P <.001), ischemic or unspecifi ed stroke (P = .03), nondisabling stroke (P = .01), and disabling or fatal stroke (P = .005). The higher dose was also associated with a 15% reduction in the risk of vascular death compared with warfarin (RR 0.85, 95% CI 0.72-0.99; P = .04), although a 12% reduction in risk of all-cause mortality did not reach statistical significance (RR 0.88, 95% CI 0.77-1.00; P = .51). Both doses of dabigatran were associated with a numerically higher risk of myocardial infarction (MI). This risk was originally reported as significantly greater with the 150-mg dose compared with warfarin (RR 1.38; 95% CI 1.00-1.91; P = 0.048). After publication of the original study, additional clinical events were discovered by the principal investigators.³⁰ Among these events were 28 instances of silent MI that were not reported by investigators during the course of the study. This finding altered the RR value in the dabigatran 150-mg dose compared with warfarin, making the RR of MI in the dabigatran 150-mg arm no longer statistically significant (RR 1.27, 95% CI 0.94-1.71; P = .12) and rendering the results somewhat less reliable. Although the authors concluded that the primary efficacy and safety conclusions of the RE-LY trial were not altered by the inclusion of these newly discovered events, these findings nonetheless reduce confidence in the reliability of the study’s findings.³⁰

The risk of major bleeding (primary safety end point), which was defi ned according to the International Society on Thrombosis and Hemostasis criteria,³¹ was reduced in the dabigatran 110-mg twice-daily group versus the warfarin group (RR 0.80; 95% CI 0.70-0.93), but was similar in frequency when the higher dabigatran dose was compared with warfarin (RR 0.93; 95% CI 0.81-1.07). Major bleeding rates per year are shown in Figure 1.²⁹ Dyspepsia was the only adverse effect that was significantly more common in the dabigatran arm, occurring in 348 patients (5.8%) in the warfarin group and in 707 patients (11.8%) and 688 patients (11.3%) in the dabigatran 110-mg and 150-mg groups, respectively (P <.001 for both comparisons). The rate of drug discontinuation for gastrointestinal (GI) symptoms was slightly higher than 2% with either dose of dabigatran and 0.6% with warfarin.²⁹

In a subsequent analysis, the rate of the primary endpoint was higher in a subgroup of patients who had experienced a previous stroke or TIA than in patients without prior stroke/TIA (2.4% per year vs 1.2% per year; P <.0001).³² In the subgroup with a prior stroke or TIA the reduction in the risk of stroke with dabigatran was mainly due to a reduction in hemorrhagic stroke, because both doses of dabigatran were associated with a significantly lower rate of intracranial bleeding versus warfarin in this subgroup. However, there was no significant interaction between previous stroke or TIA and the effects on the primary outcome with either 110-mg (P = .62) or 150-mg (P = .34) dabigatran. In patients with previous stroke/TIA, major bleeding occurred in fewer patients on 110-mg twice-daily dabigatran versus warfarin (2.7% vs 4.2% per year) and GI bleeding was more common with 150-mg twice-daily dabigatran versus warfarin (2.3% vs 1.4% per year). Because of the relatively small proportion of patients with prior stroke/TIA (20% of the total study population), the observed differences in outcomes between dabigatran and warfarin did not reach statistical significance, but the direction of effects was consistent with those seen in the overall study population.³²

There was a wide variation in INR values among participating centers in the RE-LY trial.³³ This variation may have influenced differences observed between warfarin and dabigatran. The mean warfarin recipient TTR in the RE-LY study was 64% overall, but ranged from 44% in Taiwan to 77% in Sweden.^29,33 Among warfarin recipients, there was a significant association between TTR and the primary end point of stroke or pulmonary embolism (P = .001), major bleeding (P <.0001), total mortality (P <.0001), and net clinical benefit (a composite of stroke, systemic embolism, pulmonary embolism, death, and major bleeding; P <.0001).33 Moreover, the difference between dabigatran 150 mg and warfarin for the secondary end points of nonhemorrhagic stroke and mortality was attenuated at higher quartiles of TTR (ie, better INR control), such that dabigatran 150 mg twice daily was not superior to warfarin. Dabigatran was associated with a lower rate of major bleeding versus warfarin at lower quartiles of TTR, but with a similar rate of major bleeding and a higher rate of GI bleeding at higher TTR.³³

Patients in the dabigatran arms of RE-LY were given the option to continue in an ongoing long-term extension study called RELY-ABLE. The primary end point is major bleeding, with secondary end points of stroke, non—central nervous system systemic embolism, pulmonary embolism, MI, deep vein thrombosis, all-cause mortality, and a composite of all of these. This study also includes a cluster-randomized trial of a knowledge translation intervention, which will assess its impact on patient outcomes. Caution should be used in administration of dabigatran to the elderly because conditions such as renal impairment, reduced body weight, and drug interactions may result in increased risk of major bleeding and fatality.^34,35

In most countries outside of the United States, both doses of dabigatran used in the RE-LY trial were approved by the countries’ regulatory agencies. In the United States, the FDA approved the 150-mg twice-daily dose for patients with a CrCl greater than 30 mL/min. For patients with a CrCl of 15 to 30 mL/min, the FDA approved the 75-mg twice-daily dose based on pharmacokinetic and pharmacodynamic modeling. The FDA published its rationale for its decision to approve the 150-mg twicedaily dose and not the 110-mg twice-daily dose.³⁶ A basic assumption in the FDA’s rationale was that stroke was a considerably more clinically important outcome than nonfatal and extracranial bleeding episodes. The FDA looked at 3 subgroups of patients in whom the benefits of a lower risk of bleeding might be expected to outweigh the higher risk of stroke associated with the 110-mg dose. These included patients older than age 75 years, patients with renal dysfunction, and patients with a higher risk of bleeding. In the 7238 patients in RE-LY 75 years or older, the rate of stroke and systemic embolism was 1.4 per 100 patient-years for the 150-mg dose and 1.9 per 100 patientyears for the 110-mg dose. The rate of major bleeding was higher with the 150-mg dose compared with the 110-mg dose (5.1 vs 4.4 per 100 patient-years). These rates indicate similar risk-benefit assessments of the 2 doses. In the 3343 patients in RE-LY with a CrCl of 30 to 50 mL/min, the rate of the primary composite efficacy outcome was 1.3 per 100 patient-years for the 150-mg dose compared with 2.4 per 100 patient-years for the 110-mg dose. The rate of major bleeding for the 150-mg dose was no different from the rate for the 110-mg dose (5.3 vs 5.7 per 100 patient-years). Hence, the 150-mg dose had a superior benefit-risk profile in patients with renal dysfunction. In RE-LY, 57% of patients who suffered a major bleeding event either resumed taking their study medication or had no interruption in therapy, continuing to take the same dose. The percentages of these patients who had an additional major hemorrhage were similar: 16%, 14%, and 12% in the 110-mg dabigatran, 150-mg dabigatran, and warfarin groups, respectively. These data do not support the strategy of dose reduction if patients have a bleeding event while taking a higher dose. Hence, the FDA’s decision to approve only the 150-mg strength was based on its inability to identify any subgroup in which use of the lower dose would not represent a substantial disadvantage.

Dabigatran has also been assessed for efficacy and safety in patients with acute coronary syndrome in the phase II dose-finding study Randomised Dabigatran Etexilate Dose Finding Study In Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors For Cardiovascular Complications Also Receiving Aspirin And Clopidogrel (RE-DEEM). A total of 1861 patients presenting with ST-segment elevation MI (STEMI) or non-ST-segment elevation MI (NSTEMI) and at least 1 cardiovascular risk factor were randomized to receive dabigatran (50, 75, 110, or 150 mg twice daily) or placebo in addition to standard dual antiplatelet therapy.³⁷ Following 6 months of treatment, adjuvant dabigatran treatment increased the incidence of the primary end point (composite of major or clinically relevant minor bleeding events) in a dose-dependent manner (3.5%, 4.3%, 7.9%, and 7.8% for increasing dabigatran doses and 2.2% for placebo; P <.001). There was no clear difference between the placebo and dabigatran groups for the composite of cardiovascular death, nonfatal MI, or stroke. It is currently unknown whether a phase III trial of dabigatran in acute coronary syndrome will be conducted.³⁷

Rivaroxaban

Rivaroxaban is approved for once-daily administration in patients with AF.²⁰ The efficacy of rivaroxaban for stroke prevention in patients with AF was investigated in the phase III trial ROCKET AF (Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) (

Figure 2

).^38,39 Unlike RE-LY, ROCKET AF was conducted in a double-blind fashion through use of a double-dummy double-blind technique as described by the ROCKET AF Study Investigators.³⁸ In addition, ROCKET AF enrolled a much higher risk patient population.^38,39 Qualifying criteria included prior stroke, TIA, or systemic embolism or >2 of the following risk factors: clinical heart failure or left ventricular ejection fraction <35%, hypertension, age >75 years, or diabetes mellitus (ie, a CHADS₂ score of >2). The proportion of patients who had not had a previous ischemic stroke, TIA, or systemic embolism who had <2 risk factors was capped at 10% of the cohort for each region; the remainder were required to have had either previous thromboembolism or >3 risk factors (CHADS₂ >3). As a result, 90% of patients in ROCKET-AF had a CHADS₂ score of >3 versus ~30% of patients who met the same criteria in RELY. ^36,39 The primary efficacy end point was the composite of stroke (ischemic or hemorrhagic) and systemic embolism. The principal safety end point was a composite of major and nonmajor clinically relevant bleeding events.³¹ Briefly, 14,264 patients with nonvalvular AF and increased risk for stroke were randomly assigned rivaroxaban 20 mg once daily or dose-adjusted warfarin.³⁹ The results of ROCKET AF demonstrated that in the intentionto- treat analysis, rivaroxaban was noninferior to warfarin for the prevention of subsequent stroke or systemic embolism (2.1% vs 2.4% per 100 patient-years; hazard ratio [HR] 0.88, 95% CI 0.75-1.03; P <.001 for noninferiority; P = .12 for superiority). In the per protocol population the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per 100 patient-years) and 241 in the warfarin group (2.2% per 100 patient-years; HR 0.79, 95% CI 0.66-0.96; P <.001 for noninferiority). Principal safety end point rates (major and nonmajor clinically relevant bleeding) were similar between the rivaroxaban and warfarin treatment arms (14.9% vs 14.5% per 100 patient-years; HR 1.03, 95% CI 0.96-1.11; P = .44) with significantly reduced incidents of intracranial and fatal bleeding rates (0.5% vs 0.7% and 0.2% vs 0.5%, respectively, per 100 patient-years) in the rivaroxaban group. Major bleeding was defined according to the International Society on Thrombosis and Hemostasis criteria.³¹ There was a significant increase in the number of rivaroxaban patients with a >2 g/dL reduction in hemoglobin and transfusions, which was predominantly due to a higher risk of GI bleeding (3.2% vs 2.2%, P <.001).³⁹

One notable caveat was the lower TTR with warfarin (55%) in the ROCKET AF study compared with that observed with warfarin in the other studies of the new anticoagulants in AF patients (range 64%-68%).^27,38-40 However, the TTR in ROCKET AF was closer to the rates observed outside of clinical trials or specialty clinics.¹³ This may have been a primary reason that the differences observed between warfarin and rivaroxaban were not statistically significant in the ROCKET AF study. The trials with higher warfarin TTR rates included fewer higher-risk patients than the ROCKET AF study. Patients with higher CHADS₂ scores receiving warfarin are typically more difficult to maintain in the TTR than patients with lower CHADS₂ scores.

Adverse events that occurred more frequently in patients receiving rivaroxaban during the ROCKET AF study included epistaxis and hematuria. Rivaroxaban is a substrate for both the P-gp transport protein and the CYP isozymes 3A4, 3A5, and 2J2; concomitant administration of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors may cause a significant increase in drug exposure and bleeding risk.²⁰ In addition, pharmacokinetic studies have demonstrated that patients with renal impairment may have a heightened drug response, and caution is advised when coadministering combined P-gp and weak or moderate CYP3A4 inhibitors such as diltiazem and amiodarone.^20,41,42 Patients in ROCKET AF were allowed use of combined P-gp and weak or moderate CYP3A4 inhibitors; however, no increase in bleeding was observed in patients who had a CrCl of 30 to 50 mL/min.

A similar large, randomized, phase III trial evaluating the safety of rivaroxaban for prevention of stroke and systemic embolism was conducted in 1280 Japanese patients with AF and either prior stroke, TIA, or non—central nervous system systemic embolism, or >2 risk factors for stroke (J-ROCKET AF).⁴³ Patients were randomized to rivaroxaban 15 mg once daily (10 mg once daily in patients with CrCl of 30-50 mL/min) or dose-adjusted warfarin. The 15-mg once-daily dose was chosen to address characteristics of Japanese patients and the lower anticoagulation targets of Japanese clinical practice. The primary analysis tested for noninferiority of the principal safety outcome of adjudicated major and nonmajor clinically relevant bleeding events. Although the study was powered only for the primary safety outcome, the primary efficacy end point was the composite of adjudicated stroke (ischemic and hemorrhagic) and non—central nervous system systemic embolism.⁴³

Consistent with the results of ROCKET AF, rivaroxaban was noninferior to warfarin for the primary safety outcome (18.0 vs 16.4 per 100 patient-years; HR 1.11; P <.001 for noninferiority) with fewer fatal bleeding events and intracranial hemorrhages. For the primary efficacy end point, there was a strong trend toward a reduction in stroke/systemic embolism with rivaroxaban (1.3 vs 2.6 per 100 patient-years; HR 0.49, P = .050).⁴³

Rivaroxaban has also been evaluated for safety and efficacy in patients with acute coronary syndrome in the recently completed randomized, placebo-controlled, phase III trial ATLAS ACS2-Thrombolysis in Myocardial Infarction 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51).⁴⁴ The trial enrolled 15,570 patients who had presented with symptoms suggestive of acute coronary syndrome and in whom STEMI, NSTEMI, or unstable angina had been diagnosed. In addition to standard medical therapy (low-dose aspirin and a thienopyridine), patients were randomly assigned to twice-daily administration of either 2.5 mg or 5.0 mg of rivaroxaban or placebo. The primary efficacy end point was the composite of cardiovascular death, MI, or stroke.⁴⁴

Results of the study showed that both doses of rivaroxaban significantly reduced the primary efficacy end point compared with placebo (8.9% vs 10.7%; HR 0.84,^P = .008 [combined efficacy for 2.5- and 5-mg doses]). However, compared with placebo, rivaroxab an increased the risk of major bleeding and intracranial hemorrhage, but not the risk of fatal bleeding.⁴⁴

Rivaroxaban is a potent and selective Factor Xa inhibitor with a relatively high bioavailability (~80%) and predictable pharmacokinetic/pharmacodynamic profile.²⁰ The mean half-life of rivaroxaban is 5 to 9 hours in healthy individuals, and 11 to 13 hours in the elderly. Rivaroxaban is metabolized primarily in the liver via CYP450 and CYP3A4 enzymes, and more than 30% of the drug is excreted in the feces unchanged—a process mediated, at least in part, by P-gp. Concomitant administration of rivaroxaban with strong CYP3A4 or P-gp inhibitors (eg, ritonavir, ketoconazole) significantly interferes with the metabolism of rivaroxaban and should be avoided to prevent increased drug exposure and risk of bleeding events.^20,45 Because rivaroxaban is cleared primarily by the liver and kidneys, caution should be exercised when prescribing rivaroxaban to patients with moderate to severe renal impairment (CrCl 15-30 mL/min) or hepatic impairment (Child-Pugh Class B and C).

Rivaroxaban is currently approved for stroke prevention in AF at a dose of 20 mg once daily with the evening meal, and in patients with CrCl of 15 to 50 mL/min at a dose of 15 mg once daily with the evening meal; rivaroxaban is not recommended for use in patients with a CrCl of <15 mL/min or severe hepatic impairment (Child- Pugh C) (

Table 2

).²⁰ Results of clinical studies have shown that discontinuation of rivaroxaban places patients with AF at increased risk for thrombotic events. If anticoagulation with rivaroxaban must be discontinued for a reason other than pathologic bleeding, alternative anticoagulation measures should be considered.²⁰

Apixaban

Although apixaban is not yet approved in the United States, its use for stroke prevention in patients with AF has been evaluated in 2 large-scale phase III clinical trials: ARISTOTLE (Apixaban for Reduction In Stroke and Other Thromboembolic Events) and AVERROES (Apixaban Versus Acetylsalicylic Acid to Reduce the Risk Of Stroke) (

Table 3

). Apixaban is currently approved in the European Union for thromboprophylaxis following total hip and knee replacement surgeries in adults.²¹

In the ARISTOTLE study, 18,201 patients with AF and >1 additional risk factor for stroke were randomized to receive either apixaban 5 mg twice daily or dose-adjusted warfarin (

Figure 3

).^40,48 Patient inclusion criteria were similar to those in RE-LY; eligible stroke risk factors in ARISTOTLE included age >75 years, prior stroke/TIA/systemic embolism, symptomatic congestive heart failure or left ventricular ejection fraction <40%, diabetes, and hypertension requiring treatment.^40,48 The key objective of ARISTOTLE was to demonstrate noninferiority to warfarin for the primary outcome of ischemic or hemorrhagic stroke or systemic embolism. Secondary objectives included testing for superiority with respect to the primary outcome, rates of major bleeding events, and death from any cause. Apixaban met the primary efficacy objective of noninferiority to warfarin in the ARISTOTLE trial on the combined outcome of stroke (ischemic, hemorrhagic, or unspecified type) and systemic embolism. The rate of the primary outcome was 1.27% per year in the apixaban group versus 1.60% per year in the warfarin group (HR with apixaban of 0.79; 95% CI 0.66-0.95; P <.001 for noninferiority, P = .01 for superiority).40 In addition, apixaban met the key secondary end points of superiority to warfarin with respect to the primary outcome and to the rates of major bleeding (defi ned according to the International Society on Thrombosis and Hemostasis criteria³¹) and death from any cause (2.13% per year in the apixaban group vs 3.09% per year in the warfarin group; HR 0.69, 95% CI 0.60-0.80; P <.001).⁴⁰

In the apixaban group, the rate of hemorrhagic stroke was 0.24% per year versus 0.47% per year in the warfarin group (HR 0.51, 95% CI 0.35-0.75; P <.001). Moreover, the rate of ischemic or uncertain-type stroke was 0.97% per year in the apixaban group versus 1.05% per year in the warfarin group (HR 0.92, 95% CI 0.74-1.13; P = .42).⁴⁰ Patients in the warfarin group were within the therapeutic range for a mean of 62.2% of the time after the exclusion of INR values during the first 7 days after randomization. The investigators concluded that apixaban was superior to warfarin in patients with AF for prevention of stroke or systemic embolism, decreased bleeding risk, and reduced mortality.⁴⁰

In the AVERROES trial, 5599 patients with AF (mean age 70 years) who were deemed clinically unsuitable for VKA treatment were randomized to receive apixaban (5 mg twice daily) or aspirin (81-324 mg/day) to determine whether apixaban was superior to aspirin (

Figure 4

).^47,49 The primary outcome was the occurrence of stroke or systemic embolism. The primary safety outcome was the occurrence of major bleeding. AVERROES was terminated early after an interim analysis showed a clear efficacy advantage of apixaban over the comparator (aspirin).^47,50 Briefly, a total of 51 primary outcome events (1.6% per year) were recorded in the apixaban group and 113 (3.7% per year) in the aspirin cohort (apixaban HR 0.45, 95% CI 0.32-0.62; P <.001). Death rates were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (HR 0.79, 95% CI 0.62-1.02; P = .07). Major bleeding was seen in 44 patients in the apixaban group (1.4% per year) and 39 (1.2% per year) in the aspirin group (apixaban HR 1.13, 95% CI 0.74-1.75; not significant); intracranial bleeding was seen in 11 patients in the apixaban group and 13 taking aspirin. Finally, hospitalization for cardiovascular causes was significantly reduced in the apixaban group (12.6% per year vs 15.9% per year; P <.001). It was concluded that apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage.⁴⁷ In both AVERROES and ARISTOTLE, there were no distinct side effects associated with apixaban, and patients receiving apixaban had lower rates of discontinuation than those assigned to aspirin or warfarin.^40,47

The randomized, multicenter, phase III APPRAISE-2 (Apixaban for Prevention of Acute Ischemic and Safety Events) trial evaluated apixaban for safety and efficacy in patients with acute coronary syndrome (STEMI, NSTEMI, or unstable angina). Patients were randomly assigned in a 1:1 ratio to apixaban 5 mg twice daily or placebo in addition to treatment with aspirin (acetylsalicylic acid) and clopidogrel.⁵¹ The primary end point was the composite of cardiovascular death, MI, or ischemic stroke, and the primary safety end point was major bleeding according to the Thrombolysis in Myocardial Infarction definition. ⁵² However, in November 2010, the trial was discontinued prematurely by the Data and Safety Monitoring Board because of an increase in major bleeding events with apixaban in the absence of a significant reduction in recurrent ischemic events.^51,53

Apixaban is a small-molecule inhibitor that selectively and reversibly targets Factor Xa in both its free and bound states.²² The bioavailability of apixaban is approximately 50%, with peak plasma levels reached in approximately 3 hours, resulting in a half-life of 12 hours. Similar to the other new anticoagulants, apixaban has minimal drug interactions. Concomitant use of CYP3A4 inhibitors and P-gp should be avoided because they increase the risk of bleeding events significantly. In addition, combined inducers of CYP3A4 and P-gp (eg, rifampin, phenytoin, St. John’s wort) can signifi cantly reduce antithrombotic efficacy.²²

EXPERT OPINION

The new generation of oral anticoagulants for stroke prophylaxis in AF includes a DTI (dabigatran) and 2 FXa inhibitors (rivaroxaban and apixaban). The pharmacologic profiles of these agents—including their specific targeting of single coagulation factors, a wider therapeutic window, once-daily or twice-daily fixed dosing, obviation of the need for therapeutic drug monitoring, and lower propensity for harmful drug or dietary interactions&mdash;are likely to result in significant clinical advantages over warfarin. Based on the data available from the published trials comparing the new anticoagulants with warfarin, it is not possible to reach conclusions about the relative efficacy of one agent against another. Differences in the characteristics of the study populations, the study designs of the trials, and definitions of some key study end points make cross-study comparisons impossible. In addition to different mechanisms of action, the new oral anticoagulants have different pharmacokinetic properties (Table 1), potential drug interactions, and dose-adjustment requirements in patients with renal impairment (Table 2),^{20-22,42,46,54} further hampering the possibility of any meaningful comparative analyses. Ultimately, the drug product selection and decision process will be dictated by the level of postmarketing experience, as well as the number and various types of FDA-approved indications.

Data from phase III studies and recent FDA approvals indicate that these drugs may provide promising alternatives to warfarin in the prevention of stroke in patients with AF. Dabigatran and apixaban demonstrated superior efficacy compared with warfarin in reducing stroke and systemic embolism^29,40; rivaroxaban demonstrated noninferiority to warfarin with regard to this end point.³⁹ Dabigatran 150 mg twice daily and rivaroxaban had similar rates of major hemorrhage, while dabigatran 110 mg and apixaban were shown to have lower rates of major bleeding events compared with warfarin. All of the new agents were associated with significantly lower rates of critical/ fatal and intracranial bleeding compared with warfarin.^29,39,40,47 However, dabigatran and rivaroxaban increased the risk of GI bleeding compared with warfarin, whereas apixaban did not.^29,39 Furthermore, in January 2012, the Institute for Safe Medication Practices reported FDA data from the first quarter of 2011 indicating a 19.5% increase in reports of serious, disabling, or fatal injuries associated with dabigatran therapy compared with reports from the first quarter of 2010.⁵⁵ These findings were corroborated in a multicenter observational study of periprocedural dabigatran compared with warfarin treatment in patients undergoing AF ablation.56 Results of the study showed that periprocedural dabigatran (150 mg twice daily) use for AF ablation was associated with an increased risk of bleeding and thromboembolic complications compared with warfarin (6% vs 1%; P = .019).⁵⁶

Findings from reports and studies such as the aforementioned have increased physician concerns regarding the potential risks associated with dabigatran and emphasize the need for ongoing postmarketing surveillance and adverse-event reporting to detect specific risk factors in patients that may not be apparent in a clinical trial setting. In addition, because bleeding is potentially compounded by poor renal function and low body weight, careful evaluation of the risks and benefits of dabigatran must be exercised in all patients prior to treatment.

As demonstrated in the AVERROES trial, apixaban offers clear benefits over aspirin in warfarin-intolerant or warfarin-unsuitable patients.⁴⁷ In terms of study design, ARISTOTLE and ROCKET-AF used a more rigorous approach to minimizing bias through the double-dummy and sham INR methodology.^40,48 However, many questions remain unanswered with regard to these agents. First, the reduced 75-mg dose of dabigatran approved by the FDA was never tested in RE-LY and was based solely on pharmacokinetic data modeling.⁵⁴ In addition, according to the recently updated ACCP guidelines, this dose is contraindicated in patients with severe renal impairment⁶; thus, it remains unclear whether this dose will be as efficacious as warfarin in stroke prevention. Second, the variable INR control of patients in the RELY and ROCKET AF study had an important impact on the difference between dabigatran 150 mg twice daily and rivaroxaban and warfarin.³⁰ This type of subanalysis based on the results of the ARISTOTLE trial has not been published to date. Finally, the true comparative efficacy of dabigatran, apixaban, and rivaroxaban can only be determined in head-to-head clinical trials, and it is highly unlikely that such trials will be conducted.

From a formulary perspective, the cost-effectiveness of these agents is also unclear. Warfarin is inexpensive, and its cost-effectiveness has been proved in a number of clinical trials, with substantial savings arising from prevention of strokes.^7,57,58 However, the cost-effectiveness of warfarin is highly dependent on INR control, and the need for frequent monitoring is a substantial economic burden.^7,57 Indirect costs associated with transportation to anticoagulation clinics, lost time from work, appointments, and blood tests are seldom considered in cost-effectiveness studies, which tend to focus on direct medical costs, but these may be important factors to patients.⁵⁹ Unlike warfarin, none of the new anticoagulants require monitoring—an important advantage in terms of both convenience and cost. However, the absence of necessary monitoring may not be sufficient to designate the novel agents more cost-effective than warfarin.

Recent cost-comparison analyses have indicated that dabigatran 150 mg twice daily is cost-effective compared with warfarin in AF patient populations at high risk of hemorrhage or high risk of stroke. Using a decision analysis model, Shah and Gage demonstrated that dabigatran was cost-effective versus warfarin in a hypothetical cohort of 70-year-old AF patients, based on patient criteria derived from the RE-LY study.⁶⁰ Their model showed that dabigatran was cost-effective in patients with a high stroke risk (CHADS₂ >3) and in lower-risk patients (CHADS₂ of 2) with high risk of major hemorrhage. Kamel and colleagues used a similar model to show the cost-effectiveness of dabigatran 150 mg twice daily in AF patients with prior stroke or TIA.⁶¹ However, in both studies, the cost-effectiveness of dabigatran was associated with the adequacy of warfarin INR management.

Another potential economic advantage of the new anticoagulants is improved patient compliance. Data indicate that discontinuation of warfarin is common among patients, particularly after a bleeding event and as a result of safety concerns and the economic burden of INR testing and dose adjustments. Discontinuation of treatment has been demonstrated to significantly increase healthcare costs by placing patients at high risk for stroke.⁵⁷

Despite the clinical and potential economic advantages of the new anticoagulants, complications such as bleeding remain at the forefront of physician and patient concerns due to the limited strategies available for reversal of their anticoagulant effects. Regardless of the relatively short half-lives of these agents, immediate anticoagulation reversal may be required in cases of major bleeding or emergency surgery. Prothrombin complex concentrate has been considered for use as a potential antidote due to its high concentration of clotting factors and ability to enhance thrombin generation. Eerenberg and colleagues were the first to evaluate the use of prothrombin complex concentrate for anticoagulation reversal of dabigatran and rivaroxaban in humans.⁶² The results of the clinical trial showed that the anticoagulant effect of rivaroxaban was completely reversed immediately after infusion of prothrombin complex concentrate in all subjects, whereas the anticoagulant effect of dabigatran remained unaffected. While this study may have important clinical implications, it is important to note that all tests were performed in healthy volunteers; the effect of prothrombin complex concentrate has yet to be confirmed in patients with bleeding events who are treated with these anticoagulants.⁶²

Unlike traditional anticoagulants, a defi ning disadvantage of the new agents is the absence of an antidote. Furthermore, because there are currently no definitive methods by which to monitor the anticoagulant activity and intensity of the these agents, it is important that physicians take into consideration various patient characteristics (eg, age, weight, CrCl, CHADS₂ score) and align therapy choice with clinical outcomes seen in similar patient populations.

SUMMARY

Pharmacists have an important role to play in the pharmacologic management of patients on warfarin. The identification of potential food and drug interactions, patient counseling and guidance, and frequent INR testing are all factors that must be carefully monitored during anticoagulation therapy. The new oral anticoagulants offer potential advantages over warfarin, particularly related to major hemorrhage, ease of use, and ability to maintain similar levels of protection against stroke in AF patients. However, a number of questions remain unanswered, such as the comparative effi cacy and safety of these agents relative to one another, the impact of administration schedules on compliance, and the cost-effectiveness of these agents relative to warfarin. Additional research is needed to answer these questions, and future head-to-head studies examining the efficacy of these new anticoagulants are unlikely. Ultimately, the drug product selection and decision process, as well as the number and various types of FDA-approved indications, will be important in further defining the relative efficacy and safety of these agents when used in real-world settings.