CLINICAL PRACTICE
Dabigatran etexilate: An alternative to warfarin for patients with nonvalvular atrial fibrillation Katie A. Scott, MSN (Primary Care AGNP-C)1 , & Karen A. Amirehsani, PhD, FNP-BC (Assistant Professor)2 1 2
Kernersville Primary Care, Kernersville, North Carolina Community Practice Department, The University of North Carolina at Greensboro, Greensboro, North Carolina
Keywords Dabigatran etexilate; Pradaxa; atrial fibrillation; stroke prevention. Correspondence Karen A. Amirehsani, PhD, FNP-BC, School of Nursing, The University of North Carolina at Greensboro, P. O. Box 26170, Greensboro, NC 27402-6170. Tel: 336-334-5098; Fax: 336-334-3628; E-mail: [email protected] Received: 3 June 2013; accepted: 22 July 2013 doi: 10.1002/2327-6924.12161 Disclosures: The authors report no competing interests.
Abstract Purpose: To critically appraise the evidence on dabigatran etexilate, Pradaxa, as an alternative to warfarin for stroke prevention among patients with nonvalvular atrial fibrillation. This information can assist nurse practitioners in making informed treatment decisions. Data sources: A review of the literature was conducted using CINAHL and PubMed databases. Reports published on cardiovascular organizational web sites were also searched, along with reference lists of relevant published articles and reports. Conclusions: Significant evidence from the PETRO and RE-LY trials and postmarketing analyses of dabigatran etexilate indicate that this direct thrombin inhibitor is as efficacious as warfarin in ischemic stroke prevention. In fact, the studies found that patients taking dabigatran etexilate had fewer incidences of ischemic stroke and intracranial hemorrhage than those taking warfarin. Risk for major gastrointestinal bleeding appears to be higher than that for warfarin. Implications for practice: Patients taking dabigatran etexilate do not require blood work to assess international normalized ratio (INR) levels. Because this drug is excreted primarily by the kidneys, reassessment of renal function is critical during treatment, especially with concomitant use of diuretics, fluctuating renal function, or hypovolemia. As with warfarin, nurse practitioners should educate patients about when to seek immediate care for the development of anticoagulant-associated bleeding.
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia found among the adult population in the United States (Fuster et al., 2006), and it is associated with a significantly increased risk of a thromboembolic event (Go et al., 2013). The prevalence of AF increases with age; 5.9% of adults aged 65 and above are diagnosed with AF, as compared to fewer than 0.1% of adults 55 years and younger (Go et al., 2013). The prevalence is even higher among adults 80 years of age and older; as many as 7.3%–13.7% of persons in this age group have AF (Hickey, 2012). By 2050, AF is projected to affect as many as 5.6–12 million persons in the United States (Go et al., 2013). Complications of AF include decreased cardiac output, cardiomyopathy, worsening heart failure, and the formation of thrombi. The formation of thrombi can lead to the 190
two greatest threats of AF: thromboembolism and ischemic stroke (Gutierrez & Blanchard, 2011). Persons with AF are four to five times more likely than the general adult population to have an ischemic stroke (Go et al., 2013). Additionally, AF has been identified as an independent risk factor for stroke severity, recurrence of a stroke, and mortality from a stroke (Go et al., 2013). The incidence of AFrelated stroke increases with age. Approximately 1.5% of strokes are associated with AF among individuals aged 50– 59; among those aged 80–89, the AF-related stroke rate is 23.5% (Go et al., 2013). Persons with AF who suffer strokes have poorer health outcomes and are twice as likely to have a recurrent stroke within 1 year as compared to those who have strokes unrelated to AF (Hickey, 2012). Prevention of thromboembolism is one of the primary patient management objectives for healthcare providers (American College of Cardiology Foundation [ACCF] & Journal of the American Association of Nurse Practitioners 27 (2015) 190–196 C 2014 American Association of Nurse Practitioners
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American Heart Association [AHA], 2012). Given the increasing prevalence of AF in the United States (Hickey, 2012) and the development of new antithrombotic treatments, it is essential for nurse practitioners to stay abreast of new data in order to provide appropriate treatment options to clients. The oral anticoagulant, dabigatran etexilate, marketed as Pradaxa, has been added to the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society (ACCF/AHA/ HRS) AF guidelines as an alternate modality to warfarin for ischemic stroke prevention (Wann et al., 2011). This review is designed to assist nurse practitioners in appraising the evidence on dabigatran etexilate as an alternative to warfarin for stroke prevention in patients with nonvalvular AF. The review examines the evidence on the efficacy of dabigatran etexilate for the prevention of ischemic stroke and compares it to warfarin for patients with nonvalvular AF. The review was conducted using CINAHL and PubMed databases. Additionally, reports published on cardiovascular organizational web sites were searched, along with the reference lists of relevant published articles and reports.
Clinical guidelines In the guidelines for the management of AF, the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) recommends a vitamin K antagonist with a target international normalized ratio (INR) goal of 2.0–3.0 for patients who have AF not associated with mechanical heart valves, for those at highest risk for stroke, and for those who have more than one moderate risk factor for stroke (Fuster et al., 2006). The ACC/AHA/ESC utilizes a modification of the CHADS2 (Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke [Doubled]) stroke risk index to determine the patient’s risk for stroke. The CHADS2 score is calculated by adding one point each for the presence of congestive heart failure, hypertension, age > 75 years, and diabetes. A prior history of stroke or transient ischemic attack (TIA) adds an additional two points (Fuster et al., 2006). The ACC/AHA/ESC separates risk factors into three categories: weak, moderate, and high risk. Female gender, age between 65 and 74 years, coronary artery disease, and thyrotoxicosis are considered weak risk factors. Moderate risk factors include congestive heart failure, hypertension, age ࣙ 75 years, diabetes, and left ventricular ejection fraction (EF) ࣘ 35%. High-risk factors include previous stroke, TIA, or embolism, and the presence of mitral stenosis or a prosthetic heart valve (Fuster et al., 2006). Therapy recommendations based upon the CHADS2 score consist of aspirin 81–325 mg daily for a score of 0 (low-risk factors only),
aspirin (81–325 mg daily) or warfarin for a score of 1 (one moderate risk factor), and warfarin for a score of 2 or the presence of one high-risk factor (American College of Cardiology Foundation, & American Heart Association (ACCF & AHA), 2011). Dabigatran etexilate has been added as an alternative to warfarin in patients with nonvalvular AF (ACCF & AHA, 2011). While the CHADS2 score is the gold standard for stratifying AF risk and the need for anticoagulation therapy among the general population, it does not adequately assess the risk among some populations who might be younger. For example, patients with hypertrophic cardiomyopathy (HCM) have a four- to sixfold greater risk of developing AF and consequently an ischemic stroke (Olivotto et al., 2001). In patients with HCM, the risk for AF is independent of age or the presence of diabetes, hypertension, or other comorbidities (Olivotto et al., 2001). The 2011 ACCF/AHA guidelines recommend anticoagulation therapy for all patients with HCM who have developed paroxysmal, persistent, or chronic AF (Gersh et al., 2011). A transthoracic echocardiogram is also recommended to assess thromboembolic risk in patients with HCM and in patients with rheumatic mitral valve disease (Fuster et al., 2006; Gersh et al., 2011). Dabigatran etexilate is listed as a possible alternative agent to warfarin for patients with HCM; however, evidence of usefulness in this population is lacking (Gersh et al., 2011).
Stroke prevention with warfarin Over the last two decades, ischemic stroke rates have substantially decreased among individuals receiving anticoagulation therapy (Go et al., 2013). Warfarin has been the anticoagulant of choice for more than 50 years (Grave, 2012). Although warfarin reduces stroke risk as much as 64% (Hickey, 2012), this treatment option can be complicated and risky. Warfarin has been identified as the most common medication associated with preventable hospitalizations (33.3%), primarily due to unintentional overdoses among older adults (Budnitz, Lovegrove, Shehab, & Richards, 2011). One probable cause of unintentional overdose of warfarin is difficulty in maintaining the target INR of 2.0–3.0. Maintenance of a therapeutic target requires the patient to be knowledgeable and adhere to frequent INR laboratory monitoring, warfarin dosing changes, and dietary considerations (Grave, 2012). If the INR falls to subtherapeutic levels, the risk of ischemic stroke increases. Conversely, supratherapeutic INR levels increase the patient’s risk of major bleeding events, including hemorrhagic stroke (Hickey, 2012). Also, warfarin relies on the cytochrome P450 enzyme 191
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system for metabolism and can result in dietary-drug interactions and drug–drug interactions. A 13-year cohort study of over 200,000 patients with AF on warfarin treatment examined the rates of hemorrhage and found that the first 30 days after initiation of warfarin posed the greatest risk (Gomes et al., 2013). The overall risk of hemorrhage throughout the 13-year period of the study was 3.8%; however, the risk was 11.8% during the first 30 days of warfarin treatment. Hemorrhages were classified as upper or lower gastrointestinal (GI), intracranial, or other. Incidence rates were determined based on admission to emergency rooms or hospitals for the bleeding event. GI hemorrhages were the most common (62.6%). This study identified a higher rate of hemorrhage than that reported (1%–3%) in previous clinical trials of warfarin (Gomes et al., 2013). Further, 18.1% of the hemorrhages, primarily intracranial, resulted in death within 7 days of admission.
Dabigatran etexilate (Pradaxa) Following Federal Drug Administration (FDA) approval in October 2010, dabigatran etexilate was added by the ACCF/AHA/HRS Task Force in an update to the ACC/AHA/ECS 2006 guidelines as an alternative to prevent thromboembolic events associated with AF (Wann et al., 2011). Dabigatran etexilate acts as a direct thrombin inhibitor by inhibiting free and bound thrombin, thereby halting thrombin-mediated coagulation and thrombin-induced platelet aggregation (Blommel & Blommel, 2011). The drug is eliminated primarily by the kidneys and has a half-life of 12–17 h (Boehringer Ingelheim Pharmaceuticals, Inc., 2013). The ACCF/AHA/HRS recommends dabigatran etexilate as an alternative to warfarin for patients with AF who are at risk of stroke and who do not have a mechanical heart valve, significant valve disease, creatinine clearance < 15 mL/min, or advanced liver disease causing impaired clotting function (Wann et al., 2011).
Analysis of clinical trials with dabigatran etexilate Two research trials, the Prevention of Embolic and Thrombotic Events in Patients with Persistent AF (PETRO; Ezekowitz et al., 2007) and the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY; Connolly et al., 2009), were the impetus for the approval of dabigatran etexilate as an alternative to warfarin. The PETRO trial demonstrated the safety and pharmacokinetic profile of dabigatran etexilate (Ezekowitz et al., 2007), and the RE-LY trial showed the noninferiority of dabigatran etexilate to warfarin (Connolly et al., 192
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2009). The research following the RE-LY trial has involved secondary analysis of RE-LY data based on CHADS2 score categories, postmarketing analyses, and other trials testing the efficacy and safety of dabigatran etexilate among patients with mechanical heart valves, venous thromboembolism (VTE), and myocardial infarction (MI).
PETRO trial The PETRO trial was the first study to examine dabigatran etexilate in patients with AF (Ezekowitz et al., 2007). This phase II trial compared the effects of various doses of dabigatran etexilate to identify a safe dose of the drug and examine its anticoagulant efficacy. Using a randomized controlled trial design, the investigators compared the effects of three doses of dabigatran etexilate, with and without concomitant use of aspirin, among 502 patients with AF (Ezekowitz et al., 2007). Persons with AF were eligible to participate if they had any CHADS2 risk factors. Individuals were excluded if they had mitral stenosis; a prosthetic heart valve; or recent history of MI, stroke, or TIA. Other exclusion criteria included a scheduled cardioversion, any contraindication to anticoagulation, severe renal impairment, altered liver function, or risk of pregnancy. Investigators made efforts to balance the characteristics of age, gender, history of coronary artery disease, and risk for stroke among the participants in each study group (Ezekowitz et al., 2007), thereby reducing the risk of selection bias (Tymkow, 2013). The majority of participants were male (81.9%), and the average age was 70.9 years for those with CAD and 68 years for those without CAD. Participants were randomly stratified using a 3 × 3 factorial design and were blinded to whether they were in groups receiving 50, 150, or 300 mg of dabigatran etexilate twice daily. However, participants were not blinded to concomitant use or nonuse of 81 or 325 mg of aspirin daily. The nonblinded comparator group consisted of participants taking warfarin at adjusted doses with goal INR levels of 2.0–3.0 (Ezekowitz et al., 2007). Participants were tested at baseline and returned for follow-up testing and evaluation throughout the 12-week treatment period. In order to evaluate pharmacokinetic and pharmacodynamic properties of the medication, serum drug concentration, activated partial thromboplastin time (aPTT), and D-dimer levels were monitored (Ezekowitz et al., 2007). A Wilcoxon test was used to examine suppression of D-dimer from baseline at 12 weeks in order to examine the difference between levels, determine statistically significant suppression (Ezekowitz et al., 2007), and examine test–retest
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reliability (Polit & Beck, 2012). The aPTT and D-dimer coagulation studies each evaluated a characteristic of the coagulation process: the time taken for clot formation and the presence of degradation products of clot formation, respectively (Nicoll, Lu, Pignone, & McPhee, 2012). In the PETRO trial, major bleeding events were defined as fatal or life-threatening hemorrhage, or bleeding events requiring surgery, blood transfusion, and/or resulting in a decrease in hemoglobin ࣙ 2 g/L (Ezekowitz et al., 2007). Major bleeding events occurred only in the treatment group receiving 300 mg of dabigatran etexilate with aspirin (p < .02), not in the group receiving 300 mg of dabigatran etexilate alone. The 300 and 150 mg dabigatran etexilate doses were associated with significantly (p = .002; p = .01, respectively) more bleeding events than the 50 mg dose. Only two thromboembolic events were reported, an embolism of the toe and a renal infarction, both occurred in persons in the 50 mg dose group. The 50 and 150 mg dose groups had significant increases (p = .0008; p = .027, respectively) in D-dimer concentrations, indicating lack of D-dimer suppression. The higher dose dabigatran etexilate and warfarin groups showed no significant decreases or increases in D-dimer concentration (Ezekowitz et al., 2007). In this study, higher doses of dabigatran etexilate were associated with increased incidence of major bleeding events, as well as greater suppression of D-dimer concentration. Thromboembolic events occurred only among participants receiving the lowest dose of dabigatran etexilate. The study was limited by its small sample size, short treatment duration, and lack of direct comparisons between dabigatran etexilate and warfarin. The potential for gender bias also existed because 81.9% of participants were male (Ezekowitz et al., 2007). Because aspirin has antiplatelet effects, concomitant use may have served as a confounding variable, interfering with the results (Tymkow, 2013).
RE-LY trial The RE-LY trial was a large, multicenter, phase III study directly comparing dabigatran etexilate to warfarin (Connolly et al., 2009) that ultimately led to FDA approval of the new anticoagulant agent and the new ACCF/AHA/HRS recommendations (Wann et al., 2011). By comparing dabigatran etexilate to warfarin, the researchers hoped to show that dabigatran etexilate was not inferior to warfarin as an oral anticoagulant for patients with AF (Ezekowitz et al., 2009). They used the same eligibility and exclusion criteria used in the PETRO study and planned to enroll at least 18,000 patients to achieve statistical power (Ezekowitz et al., 2007, 2009). Over a 24-month period, 18,113 patients from 951 clinical cen-
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ters in 44 countries participated; the average age of participants was 71 years; over half were male, and their average CHADS2 score was 2.1 (Connolly et al., 2009). Participants were randomly placed into one of three groups: blinded doses of 110 or 150 mg of dabigatran etexilate twice daily or a nonblinded dose of 1, 3, or 5 mg of warfarin adjusted for the INR goal of 2.0–3.0 (Connolly et al., 2009). While the PETRO study monitored coagulation values, the RE-LY trial determined results based on outcome events, specifically stroke, systemic embolism, and major hemorrhage. To prevent bias, two independent investigators reviewed documents to identify outcome events, using blinded review. This was important considering the risk of bias associated with the open-label warfarin control group (Connolly et al., 2009). Further efforts to increase validity included random assignment of treatment groups and control of possible confounding variables (Tymkow, 2013). To reduce the risk that a patient’s previous exposure to warfarin would influence study results, equal enrollment of the warfarin-experienced and the warfarin-na¨ıve was enforced (Connolly et al., 2009). Because this was a trial comparing dabigatran etexilate to warfarin (Connolly et al., 2009), the researchers needed to demonstrate that dabigatran etexilate was no worse than warfarin in a predetermined, clinically important amount (Polit & Beck, 2012). The researchers utilized Cox proportional hazards modeling and set the noninferiority margin at 1.46 based on previous placebo trials with warfarin. To prove noninferiority, the hazard ratio of dabigatran etexilate compared to warfarin needed to be less than 1.46 (p < .0125) based on a 97.5% confidence interval (CI; Ezekowitz et al., 2009). Relative risks (RRs), CI, and p values were determined by Cox regression, and medication discontinuation and adverse events were compared with chi-square tests (Connolly et al., 2009). The incidence of stroke and systemic embolism was significantly lower (p < .001) for participants receiving dabigatran etexilate doses of 110 or 150 mg than for persons receiving warfarin, demonstrating noninferiority. The 150 mg dose of dabigatran showed superiority to warfarin in the prevention of ischemic stroke (RR, 0.66; 95% CI, 0.53–0.82; p < .001). Hemorrhagic stroke was significantly lower in participants receiving either dose of dabigatran etexilate (p < .001) than in the warfarin group. The 110 mg dose was associated with a significantly lower incidence of bleeding (RR, 0.80; 95% CI, 0.69–0.93; p = .003), but the 150 mg dose was not (RR, 0.93; 95% CI, 0.81–1.07; p = .31). The 150 mg dose decreased the risk of ischemic stroke (p = .005), but was associated with increased risk for major bleeding in patients ࣙ 75 years of age. Dyspepsia was the only adverse effect
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significantly (p < .001) more prevalent in the dabigatran etexilate groups (Connolly et al., 2009). Overall, results from the RE-LY trial indicated that dabigatran etexilate is noninferior to warfarin and provided evidence that a 110 mg dose is associated with decreased incidence of major bleeding (Connolly et al., 2009). This was a more extensive study than the PETRO trial, with a larger sample from multiple centers in many countries, longer duration of treatment, and direct comparisons between dabigatran etexilate and warfarin. However, the potential that aspirin would serve as a confounding variable was not completely eliminated, because concomitant use was neither enforced nor prevented (Connolly et al., 2009). INR levels in the control group may also have influenced results, because INR levels were therapeutic only 64.2% of the time (Blommel & Blommel, 2011), and strict adherence to warfarin dose-adjustment algorithms was not enforced (Connolly et al., 2009).
Secondary analysis of RE-LY data Subgroup analysis of vitamin K antagonist experienced and vitamin K antagonist na¨ıve patients indicated that both populations had a significantly lower risk for ischemic stroke with the 150 mg dose of dabigatran etexilate than with warfarin (RR, 0.66; 95% CI, 0.49–0.89; p = .007 and RR, 0.63; 95% CI, 0.46–0.87; p = .005, respectively), indicating the benefit of switching patients on warfarin to dabigatran etexilate (Ezekowitz et al., 2010). A secondary analysis of the RE-LY data categorizing patients based on CHADS2 score indicated that the 150 mg dose of dabigatran etexilate was most beneficial for participants with the highest CHADS2 scores (Oldgren, Alings et al., 2011). Dabigatran etexilate has an approximate cost of $6.75– $8.00 per day, compared to a total yearly cost of $50 for warfarin (Wartak & Bartholomew, 2011). Freeman et al. (2011) examined data from the RE-LY trial to compare the cost-effectiveness of dabigatran etexilate to warfarin in a hypothesized population of patients 65 years old and older with AF and with a CHADS2 score ࣙ 1. Warfarin was compared to 110 and 150 mg twice daily doses of dabigatran etexilate to determine net cost over 35 years, or until death, and quality of life was compared based on risk for adverse events. While the total cost of 150 mg dabigatran etexilate ($168,398) exceeded the total cost of warfarin ($143,193), quality-adjusted life-years (QALYs) were higher with dabigatran etexilate (10.84) than with warfarin (10.28), indicating that dabigatran etexilate was more cost-effective. Dabigatran etexilate was more cost-effective than warfarin for patients at highest risk for ischemic and hemorrhagic stroke (Freeman et al., 2011). 194
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Postmarketing data on dabigatran etexilate Since FDA approval in October 2010, more than 3.5 million prescriptions of dabigatran etexilate have been dispensed, with approximately 725,000 patients receiving this medication from U.S. outpatient retail pharmacies (Food and Drug Administration [FDA], 2012). A higher than expected number of serious bleeding events among dabigatran etexilate users has been reported to the FDA Adverse Event Reporting System, resulting in further investigation of the safety of this anticoagulant (FDA, 2012; Southworth, Reichman, & Unger, 2013). The FDA conducted a review of actual GI and intracranial bleeding events using their Mini-Sentinel Database, which compares new users of dabigatran etexilate with new users of warfarin to determine if the reports received postmarketing represent true increased bleeding risk for dabigatran etexilate as compared to warfarin (FDA, 2012). After reviewing the data, the FDA found lower incidence rates of GI and intracranial hemorrhage among new users of dabigatran etexilate than among new users of warfarin and no recommended changes were made for the use of dabigatran etexilate (FDA, 2012; Southworth et al., 2013). Reasons for higher reported bleeding events considered by the FDA include greater likelihood of reporting a bleeding event with a novelty drug than with the long-used warfarin, failure of providers to make dosage adjustments for patients with impaired renal function, and different use of dabigatran etexilate postmarketing than in the RE-LY trial (FDA, 2012; Southworth et al., 2013). Recently released postmarketing analyses by the FDA of 134,000 Medicare patients, aged 65 or above, indicate that new users of dabigatran as compared to warfarin have a lower risk for embolic stroke, intracranial hemorrhage, and death (FDA, 2014). Additionally, the risk for MI was the same for users taking both drugs. However, a higher incidence of major GI bleeding was noted among dabigatran users as compared to warfarin. No new FDA recommendations were made for drug use or labeling (FDA, 2014). Berger, Salhanick, Chase, and Ganetsky (2013) conducted a prospective cohort chart review of emergency department patients presenting at an urban tertiary hospital with a hemorrhage while taking either dabigatran etexilate (n = 15) or warfarin (n = 123) during a 6-month period in 2011. The findings from this study indicated that GI hemorrhages were the most common bleeding event for both dabigatran etexilate (80%) and warfarin (48%) groups. Only patients receiving warfarin were found to have intracranial hemorrhages. Patients presenting with dabigatran etexilate related bleeding were older (77 vs. 70 years), had a shorter length of stay (3.5 vs. 6.0 days), and received fewer packed RBC transfusions (1.1 vs. 2.3 units)
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and fewer units of fresh frozen plasma (0.3 vs. 1.1 units) than those with warfarin-related bleeding. More than half (53%) of the group receiving dabigatran etexilate had suffered some kind of acute renal injury, defined as ࣙ 50% increase in serum creatinine level or ࣙ 0.3 mg/dL absolute increase in serum creatinine level, compared to 42% of those receiving warfarin. Additional trials have been conducted to study the efficacy and safety of dabigatran etexilate. The RE-ALIGN research trial evaluated the use of dabigatran etexilate in patients with AF and a mechanical heart valve (Van de Werf et al., 2012). However, the study was terminated early due to greater risk for stroke, MI, embolism, and bleeding events among patients receiving dabigatran etexilate than among those receiving warfarin. The FDA has since mandated that dabigatran etexilate is contraindicated for patients with a mechanical heart valve (FDA, 2013). The RE-DEEM trial evaluated the safety and efficacy of dabigatran etexilate when given with a dual antiplatelet treatment to patients who had a recent MI (Oldgren, Budaj et al., 2011). Dabigatran etexilate was associated with a reduction in coagulation activity but also with a dose-dependent increase in bleeding events. The net clinical benefit of dabigatran etexilate among patients with a recent MI could not be concluded (Oldgren, Budaj et al., 2011). The RE-MEDY and RE-SONATE trials compared the safety and efficacy of dabigatran etexilate with warfarin or placebo, respectively, in patients with a history of VTE (Schulman et al., 2013). In the RE-MEDY and RE-SONATE trials, dabigatran etexilate was found to be effective in the long-term treatment of VTE and noninferior to warfarin. However, in comparison to warfarin (RE-MEDY trial) but not placebo (RE-SONATE trial), patients receiving dabigatran etexilate had an increased incidence of MI, reasons for this finding are not clear (Schulman et al., 2013). Dabigatran etexilate has not been approved for the treatment of VTE (Blommel & Blommel, 2011).
Implications for practice This review provides evidence to assist nurse practitioners and other healthcare professionals to make an informed decision about the use of dabigatran etexilate for the management of nonvalvular AF. Dabigatran etexilate has been shown to be associated with a less complicated patient management regimen than warfarin. Frequent monitoring of INR is not required. There are fewer interacting drugs and foods, because the drug does not depend on the cytochrome P450 enzyme system for metabolism (Grave, 2012). Currently, the FDA recommends 150 mg of dabigatran etexilate twice daily unless creatinine clearance is 15–30 mL/min; for those patients,
75 mg twice daily is recommended, because the drug is excreted primarily unchanged by the kidneys (Blommel & Blommel, 2011). It is important to note that testing of the 75 mg dose was not reported in either the PETRO (Ezekowitz et al., 2007) or RE-LY (Connolly et al., 2009) trials. The FDA recommends that healthcare professionals reassess renal function during treatment, particularly with concomitant diuretic use, episodes of fluctuating renal function, or hypovolemia, and make necessary dose adjustments (FDA, 2012). As with warfarin, nurse practitioners should provide patients with written directions about when to seek immediate care for the development of the signs and symptoms of anticoagulant-associated bleeding (FDA, 2012). Unlike warfarin, dabigatran etexilate does not have a specific reversal agent for bleeding (Blommel & Blommel, 2011). The increased incidence of dyspepsia and twice-daily dosing requirements with dabigatran etexilate do raise the potential for medication nonadherence (Grave, 2012). However, with careful patient selection along with patient education, encouraging dedication to the medication regimen and reporting of adverse effects, dabigatran etexilate can be effectively used as a warfarin alternative. Because the drug is new and its associated long-term clinical course is not completely known, nurse practitioners should be on the lookout for further studies and FDA announcements.
Conclusion Significant evidence from the PETRO and RE-LY trials and postmarketing analyses of dabigatran etexilate indicate that this direct thrombin inhibitor is efficacious and a noninferior alternative to warfarin for the prevention of ischemic stroke in patients with nonvalvular AF who meet the ACCF/AHA/HRS criteria. Findings from the RE-LY trial indicate that twice daily dosing of 150 mg of dabigatran etexilate is superior to warfarin for the prevention of ischemic stroke and patients taking dabigatran etexilate suffer a lower incidence of intracranial hemorrhage than those taking warfarin (Connolly et al., 2009). Risk for dabigatran etexilate related GI bleeding appears to be higher than that for warfarin (FDA, 2014). The research conducted on dabigatran is sound, reliable, and has included samples representative of the population who should receive warfarin anticoagulation according to current guidelines (Wann et al., 2011). Findings from the aborted RE-ALIGN trial reinforce that dabigatran etexilate is contraindicated in those with prosthetic mechanical heart valves (Van de Werf et al., 2012) and it is currently not recommended for VTE prophylaxis or post-MI (Blommel & Blommel, 2011; Oldgren, Budaj et al., 2011; Schulman et al., 2013). 195
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References American College of Cardiology Foundation, & American Heart Association (ACCF & AHA). (2011). ACCF/AHA pocket guideline: Management of patients with atrial fibrillation (Adapted from the 2006 ACCF/AHA/ESC Guideline and the 2011 ACCF/AHA/HRS focused updates). Retrieved from http://my. americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@spub/ documents/downloadable/ucm 427314.pdf Berger, R., Salhanick, S. D., Chase, M., & Ganetsky, M. (2013). Hemorrhagic complications in emergency department patients who are receiving dabigatran compared with warfarin. Annals of Emergency Medicine, 61(4), 475–479. doi:10.1016/j.annemergmed.2013.02.008 Blommel, M. L., & Blommel, A. L. (2011). Dabigatran etexilate: A novel oral direct thrombin inhibitor. American Journal of Health-System Pharmacy, 68, 1506–1519. doi:10.2146/ajhp100348 Boehringer Ingelheim Pharmaceuticals, Inc. (2013). Pradaxa : Highlights of prescribing information. Retrieved from http://bidocs.boehringeringelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt& folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf Budnitz, D. S., Lovegrove, M. C., Shehab, N., & Richards, C. L. (2011). Emergency hospitalizations for adverse drug events in older Americans. New England Journal of Medicine, 365(21), 2002–2012. Connolly, S. J., Ezekowitz, M. D., Yusuf, S., Eikelboom, J., Oldgren, J., & Parekh, Wallentin, L. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 361(12), 1139–1151. doi:10.1056/NEJMoa0905561 Ezekowitz, M. D., Connolly, S., Parekh, A., Reilly, P. A., Varrone, J., Wang, S., & Wallentin, L. (2009). Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. American Heart Journal, 57(5), 805–810. doi:10.1016/j.ahj.2009.02.005 Ezekowitz, M. D., Reilly, P. A., Nehmiz, G., Simmers, T. A., Nagarakanti, R., Parcham-Azad, K., & Wallentin, L. (2007). Dabigatran with or without concomitant aspirin compared with warfarin along in patients with nonvalvular atrial fibrillation (PETRO study). American Journal of Cardiology, 100(9), 1419–1426. doi:10.1016/j.amjcard.2007.06.034 Ezekowitz, M. D., Wallentin, L., Connolly, S. J., Parekh, A., Chernick, M. R., Pogue, J., & Yusuf, S. (2010). Dabigatran and warfarin in vitamin K antagonist-na¨ıve and experienced cohorts with atrial fibrillation. Circulation, 122(22), 2246–2253. doi:10.1161/CIRCULATIONAHA.110.973735 Food and Drug Administration (FDA). (2012, November 2). FDA drug safety communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran). Retrieved from http://www.fda.gov/ Drugs/DrugSafety/ucm326580.htm Food and Drug Administration. (2013, February 15). FDA drug safety communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves. Retrieved from http://www. fda.gov/Drugs/DrugSafety/ucm332912.htm Food and Drug Administration. (2014, May 13). Pradaxa (dabigatran): Drug safety communication—Lower risk for stroke and death, but higher risk for GI bleeding compared to warfarin. Retrieved from http://www.fda.gov/safety/ medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ ucm397179.htm Freeman, J. V., Zhu, R. P., Owens, D. K., Garber, A. M., Hutton, D. W., Go, A. S., & Turakhia, M. P. (2011). Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Annals of Internal Medicine, 154(1), 1–11. doi:10.1059/0003-4819-154-1-201101040-00289 ´ L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, Fuster, W., Ryden, R. A., & Wann, S. (2006). ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—Executive summary. Journal of American College of Cardiology, 48(4), 854–906. doi:10.1016/j.jacc. 2006.07.009 Gersh, B. J., Maron, B. J., Bonow, R. O., Dearani, J. A., Fifer, M. A., Link, M. S., & Yancy, C. W. (2011). 2011 ACCF/AHA guideline for the diagnosis and R
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treatment of hypertrophic cardiomyopathy: Executive summary—A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation, 124, 1–36. doi:10.1161/CIR.0b013e318223e230 Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Borden, W. B., & Turner, M. B. (2013). Heart disease and stroke statistics – 2013 update: A report from the American Heart Association. Circulation, 127, e6–e245. doi:10.1161/CIR.0b013e31828124ad Gomes, T., Mamdani, M. M., Holbrook, A., Paterson, J. M., Hellings, C., & Juurlink, D. N. (2013). Rates of hemorrhage during warfarin therapy for atrial fibrillation. Canadian Medical Association Journal, 185(2), e121-e127. doi:10.1503/cmaj.121218 Grave, S. (2012). Dabigatran versus warfarin for patients with non-valvular atrial fibrillation: Is the patient the winner? Australian Nursing Journal, 19(6), 30–33. Gutierrez, C., & Blanchard, D. G. (2011). Atrial fibrillation: Diagnosis and treatment. American Family Physician, 83(1), 61–68. Retrieved from http://www.aafp.org/afp/2011/0101/p61.pdf Hickey, K. (2012). Anticoagulation management in clinical practice: Preventing stroke in patients with atrial fibrillation. Heart & Lung, 41, 146–156. doi:10.1016/j.hrtlng.2011.07.008 Nicoll, D., Lu, C. M., Pignone, M., & McPhee, S. J. (2012). Pocket guide to diagnosis tests (6th ed.) New York: McGraw Hill Medical. Oldgren, J., Alings, M., Darius, H., Diener, H., Eikelboom, J., Ezekowitz, M. D., & Connolly, S. J. (2011). Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: A subgroup analysis of the RE-LY trial. Annals of Internal Medicine, 155, 660–667. Retrieved from www.annals.org Oldgren, J., Budaj, A., Granger, C. B., Khder, Y., Roberts, J., Siegbahn, A., & Wallentin, L. (2011). Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: A randomized, double-blind, phase II trial. European Heart Journal, 32(22), 2781–2789. doi:10.1093/eurheartj.ehr113 Olivotto, I., Cecchi, F., Casey, S. A., Dolara, A., Traverse, J. H., & Maron, B. J. (2001). Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation, 104, 2517–2524. doi:10.1161/hc4601.097997 Polit, D. F., & Beck, C. T. (2012). Nursing research: Generating and assessing evidence for nursing practice (9th ed.). Philadelphia, PA: Lippincott Williams & Wilkins. Schulman, S., Kearon, C., Kakkar, A. K., Schellong, S., Eriksson, H., Baanstra, D., & Goldhaber, S. Z. (2013). Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. New England Journal of Medicine, 368(8), 709–718. doi:10.1056/NEJMoa1113697 Southworth, M. R., Reichman, M. E., & Unger, E. F. (2013). Dabigatran and postmarketing reports of bleeding. New England Journal of Medicine, 368(14), 1272–1274. doi:10.1056/NEJMp1302834 Tymkow, C. (2013). Clinical scholarship and evidence-based practice. In S. M. DeNisco & A. M. Barker (Eds.), Advanced practice nursing: Evoking roles for the transformation of the profession (pp. 423–477). Burlington, MA: Jones and Bartlett Learning. Van de Werf, F., Brueckmann, M., Connolly, S. J., Friedman, J., Granger, ¨ C. B., Hartter, S., & Eikelboom, J. W. (2012). A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). American Heart Journal, 163(6), 931–937. doi:10.1016/j.ahj. 2012.03.011 Wann, L. S., Curtis, A. B., Ellenbogen, K. A., Estes, M., Ezekowitz, M. D., Jackman, W. M., & Tracy, C. M. (2011). 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update of dabigatran). Circulation, 1144–1150. doi:10.1161/CIR.0B013e31820f14c0 Wartak, S. A., & Bartholomew, J. R. (2011). Dabigatran: Will it change clinical practice? Cleveland Clinic Journal of Medicine, 78(10), 657–662. doi:10.3949/ccjm.78a.11021
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Dabigatran etexilate: An alternative to warfarin for patients with nonvalvular atrial fibrillation Katie A. Scott, MSN (Primary Care AGNP-C)1 , & Karen A. Amirehsani, PhD, FNP-BC (Assistant Professor)2 1 2
Kernersville Primary Care, Kernersville, North Carolina Community Practice Department, The University of North Carolina at Greensboro, Greensboro, North Carolina
Keywords Dabigatran etexilate; Pradaxa; atrial fibrillation; stroke prevention. Correspondence Karen A. Amirehsani, PhD, FNP-BC, School of Nursing, The University of North Carolina at Greensboro, P. O. Box 26170, Greensboro, NC 27402-6170. Tel: 336-334-5098; Fax: 336-334-3628; E-mail: [email protected] Received: 3 June 2013; accepted: 22 July 2013 doi: 10.1002/2327-6924.12161 Disclosures: The authors report no competing interests.
Abstract Purpose: To critically appraise the evidence on dabigatran etexilate, Pradaxa, as an alternative to warfarin for stroke prevention among patients with nonvalvular atrial fibrillation. This information can assist nurse practitioners in making informed treatment decisions. Data sources: A review of the literature was conducted using CINAHL and PubMed databases. Reports published on cardiovascular organizational web sites were also searched, along with reference lists of relevant published articles and reports. Conclusions: Significant evidence from the PETRO and RE-LY trials and postmarketing analyses of dabigatran etexilate indicate that this direct thrombin inhibitor is as efficacious as warfarin in ischemic stroke prevention. In fact, the studies found that patients taking dabigatran etexilate had fewer incidences of ischemic stroke and intracranial hemorrhage than those taking warfarin. Risk for major gastrointestinal bleeding appears to be higher than that for warfarin. Implications for practice: Patients taking dabigatran etexilate do not require blood work to assess international normalized ratio (INR) levels. Because this drug is excreted primarily by the kidneys, reassessment of renal function is critical during treatment, especially with concomitant use of diuretics, fluctuating renal function, or hypovolemia. As with warfarin, nurse practitioners should educate patients about when to seek immediate care for the development of anticoagulant-associated bleeding.
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia found among the adult population in the United States (Fuster et al., 2006), and it is associated with a significantly increased risk of a thromboembolic event (Go et al., 2013). The prevalence of AF increases with age; 5.9% of adults aged 65 and above are diagnosed with AF, as compared to fewer than 0.1% of adults 55 years and younger (Go et al., 2013). The prevalence is even higher among adults 80 years of age and older; as many as 7.3%–13.7% of persons in this age group have AF (Hickey, 2012). By 2050, AF is projected to affect as many as 5.6–12 million persons in the United States (Go et al., 2013). Complications of AF include decreased cardiac output, cardiomyopathy, worsening heart failure, and the formation of thrombi. The formation of thrombi can lead to the 190
two greatest threats of AF: thromboembolism and ischemic stroke (Gutierrez & Blanchard, 2011). Persons with AF are four to five times more likely than the general adult population to have an ischemic stroke (Go et al., 2013). Additionally, AF has been identified as an independent risk factor for stroke severity, recurrence of a stroke, and mortality from a stroke (Go et al., 2013). The incidence of AFrelated stroke increases with age. Approximately 1.5% of strokes are associated with AF among individuals aged 50– 59; among those aged 80–89, the AF-related stroke rate is 23.5% (Go et al., 2013). Persons with AF who suffer strokes have poorer health outcomes and are twice as likely to have a recurrent stroke within 1 year as compared to those who have strokes unrelated to AF (Hickey, 2012). Prevention of thromboembolism is one of the primary patient management objectives for healthcare providers (American College of Cardiology Foundation [ACCF] & Journal of the American Association of Nurse Practitioners 27 (2015) 190–196 C 2014 American Association of Nurse Practitioners
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American Heart Association [AHA], 2012). Given the increasing prevalence of AF in the United States (Hickey, 2012) and the development of new antithrombotic treatments, it is essential for nurse practitioners to stay abreast of new data in order to provide appropriate treatment options to clients. The oral anticoagulant, dabigatran etexilate, marketed as Pradaxa, has been added to the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society (ACCF/AHA/ HRS) AF guidelines as an alternate modality to warfarin for ischemic stroke prevention (Wann et al., 2011). This review is designed to assist nurse practitioners in appraising the evidence on dabigatran etexilate as an alternative to warfarin for stroke prevention in patients with nonvalvular AF. The review examines the evidence on the efficacy of dabigatran etexilate for the prevention of ischemic stroke and compares it to warfarin for patients with nonvalvular AF. The review was conducted using CINAHL and PubMed databases. Additionally, reports published on cardiovascular organizational web sites were searched, along with the reference lists of relevant published articles and reports.
Clinical guidelines In the guidelines for the management of AF, the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) recommends a vitamin K antagonist with a target international normalized ratio (INR) goal of 2.0–3.0 for patients who have AF not associated with mechanical heart valves, for those at highest risk for stroke, and for those who have more than one moderate risk factor for stroke (Fuster et al., 2006). The ACC/AHA/ESC utilizes a modification of the CHADS2 (Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke [Doubled]) stroke risk index to determine the patient’s risk for stroke. The CHADS2 score is calculated by adding one point each for the presence of congestive heart failure, hypertension, age > 75 years, and diabetes. A prior history of stroke or transient ischemic attack (TIA) adds an additional two points (Fuster et al., 2006). The ACC/AHA/ESC separates risk factors into three categories: weak, moderate, and high risk. Female gender, age between 65 and 74 years, coronary artery disease, and thyrotoxicosis are considered weak risk factors. Moderate risk factors include congestive heart failure, hypertension, age ࣙ 75 years, diabetes, and left ventricular ejection fraction (EF) ࣘ 35%. High-risk factors include previous stroke, TIA, or embolism, and the presence of mitral stenosis or a prosthetic heart valve (Fuster et al., 2006). Therapy recommendations based upon the CHADS2 score consist of aspirin 81–325 mg daily for a score of 0 (low-risk factors only),
aspirin (81–325 mg daily) or warfarin for a score of 1 (one moderate risk factor), and warfarin for a score of 2 or the presence of one high-risk factor (American College of Cardiology Foundation, & American Heart Association (ACCF & AHA), 2011). Dabigatran etexilate has been added as an alternative to warfarin in patients with nonvalvular AF (ACCF & AHA, 2011). While the CHADS2 score is the gold standard for stratifying AF risk and the need for anticoagulation therapy among the general population, it does not adequately assess the risk among some populations who might be younger. For example, patients with hypertrophic cardiomyopathy (HCM) have a four- to sixfold greater risk of developing AF and consequently an ischemic stroke (Olivotto et al., 2001). In patients with HCM, the risk for AF is independent of age or the presence of diabetes, hypertension, or other comorbidities (Olivotto et al., 2001). The 2011 ACCF/AHA guidelines recommend anticoagulation therapy for all patients with HCM who have developed paroxysmal, persistent, or chronic AF (Gersh et al., 2011). A transthoracic echocardiogram is also recommended to assess thromboembolic risk in patients with HCM and in patients with rheumatic mitral valve disease (Fuster et al., 2006; Gersh et al., 2011). Dabigatran etexilate is listed as a possible alternative agent to warfarin for patients with HCM; however, evidence of usefulness in this population is lacking (Gersh et al., 2011).
Stroke prevention with warfarin Over the last two decades, ischemic stroke rates have substantially decreased among individuals receiving anticoagulation therapy (Go et al., 2013). Warfarin has been the anticoagulant of choice for more than 50 years (Grave, 2012). Although warfarin reduces stroke risk as much as 64% (Hickey, 2012), this treatment option can be complicated and risky. Warfarin has been identified as the most common medication associated with preventable hospitalizations (33.3%), primarily due to unintentional overdoses among older adults (Budnitz, Lovegrove, Shehab, & Richards, 2011). One probable cause of unintentional overdose of warfarin is difficulty in maintaining the target INR of 2.0–3.0. Maintenance of a therapeutic target requires the patient to be knowledgeable and adhere to frequent INR laboratory monitoring, warfarin dosing changes, and dietary considerations (Grave, 2012). If the INR falls to subtherapeutic levels, the risk of ischemic stroke increases. Conversely, supratherapeutic INR levels increase the patient’s risk of major bleeding events, including hemorrhagic stroke (Hickey, 2012). Also, warfarin relies on the cytochrome P450 enzyme 191
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system for metabolism and can result in dietary-drug interactions and drug–drug interactions. A 13-year cohort study of over 200,000 patients with AF on warfarin treatment examined the rates of hemorrhage and found that the first 30 days after initiation of warfarin posed the greatest risk (Gomes et al., 2013). The overall risk of hemorrhage throughout the 13-year period of the study was 3.8%; however, the risk was 11.8% during the first 30 days of warfarin treatment. Hemorrhages were classified as upper or lower gastrointestinal (GI), intracranial, or other. Incidence rates were determined based on admission to emergency rooms or hospitals for the bleeding event. GI hemorrhages were the most common (62.6%). This study identified a higher rate of hemorrhage than that reported (1%–3%) in previous clinical trials of warfarin (Gomes et al., 2013). Further, 18.1% of the hemorrhages, primarily intracranial, resulted in death within 7 days of admission.
Dabigatran etexilate (Pradaxa) Following Federal Drug Administration (FDA) approval in October 2010, dabigatran etexilate was added by the ACCF/AHA/HRS Task Force in an update to the ACC/AHA/ECS 2006 guidelines as an alternative to prevent thromboembolic events associated with AF (Wann et al., 2011). Dabigatran etexilate acts as a direct thrombin inhibitor by inhibiting free and bound thrombin, thereby halting thrombin-mediated coagulation and thrombin-induced platelet aggregation (Blommel & Blommel, 2011). The drug is eliminated primarily by the kidneys and has a half-life of 12–17 h (Boehringer Ingelheim Pharmaceuticals, Inc., 2013). The ACCF/AHA/HRS recommends dabigatran etexilate as an alternative to warfarin for patients with AF who are at risk of stroke and who do not have a mechanical heart valve, significant valve disease, creatinine clearance < 15 mL/min, or advanced liver disease causing impaired clotting function (Wann et al., 2011).
Analysis of clinical trials with dabigatran etexilate Two research trials, the Prevention of Embolic and Thrombotic Events in Patients with Persistent AF (PETRO; Ezekowitz et al., 2007) and the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY; Connolly et al., 2009), were the impetus for the approval of dabigatran etexilate as an alternative to warfarin. The PETRO trial demonstrated the safety and pharmacokinetic profile of dabigatran etexilate (Ezekowitz et al., 2007), and the RE-LY trial showed the noninferiority of dabigatran etexilate to warfarin (Connolly et al., 192
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2009). The research following the RE-LY trial has involved secondary analysis of RE-LY data based on CHADS2 score categories, postmarketing analyses, and other trials testing the efficacy and safety of dabigatran etexilate among patients with mechanical heart valves, venous thromboembolism (VTE), and myocardial infarction (MI).
PETRO trial The PETRO trial was the first study to examine dabigatran etexilate in patients with AF (Ezekowitz et al., 2007). This phase II trial compared the effects of various doses of dabigatran etexilate to identify a safe dose of the drug and examine its anticoagulant efficacy. Using a randomized controlled trial design, the investigators compared the effects of three doses of dabigatran etexilate, with and without concomitant use of aspirin, among 502 patients with AF (Ezekowitz et al., 2007). Persons with AF were eligible to participate if they had any CHADS2 risk factors. Individuals were excluded if they had mitral stenosis; a prosthetic heart valve; or recent history of MI, stroke, or TIA. Other exclusion criteria included a scheduled cardioversion, any contraindication to anticoagulation, severe renal impairment, altered liver function, or risk of pregnancy. Investigators made efforts to balance the characteristics of age, gender, history of coronary artery disease, and risk for stroke among the participants in each study group (Ezekowitz et al., 2007), thereby reducing the risk of selection bias (Tymkow, 2013). The majority of participants were male (81.9%), and the average age was 70.9 years for those with CAD and 68 years for those without CAD. Participants were randomly stratified using a 3 × 3 factorial design and were blinded to whether they were in groups receiving 50, 150, or 300 mg of dabigatran etexilate twice daily. However, participants were not blinded to concomitant use or nonuse of 81 or 325 mg of aspirin daily. The nonblinded comparator group consisted of participants taking warfarin at adjusted doses with goal INR levels of 2.0–3.0 (Ezekowitz et al., 2007). Participants were tested at baseline and returned for follow-up testing and evaluation throughout the 12-week treatment period. In order to evaluate pharmacokinetic and pharmacodynamic properties of the medication, serum drug concentration, activated partial thromboplastin time (aPTT), and D-dimer levels were monitored (Ezekowitz et al., 2007). A Wilcoxon test was used to examine suppression of D-dimer from baseline at 12 weeks in order to examine the difference between levels, determine statistically significant suppression (Ezekowitz et al., 2007), and examine test–retest
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reliability (Polit & Beck, 2012). The aPTT and D-dimer coagulation studies each evaluated a characteristic of the coagulation process: the time taken for clot formation and the presence of degradation products of clot formation, respectively (Nicoll, Lu, Pignone, & McPhee, 2012). In the PETRO trial, major bleeding events were defined as fatal or life-threatening hemorrhage, or bleeding events requiring surgery, blood transfusion, and/or resulting in a decrease in hemoglobin ࣙ 2 g/L (Ezekowitz et al., 2007). Major bleeding events occurred only in the treatment group receiving 300 mg of dabigatran etexilate with aspirin (p < .02), not in the group receiving 300 mg of dabigatran etexilate alone. The 300 and 150 mg dabigatran etexilate doses were associated with significantly (p = .002; p = .01, respectively) more bleeding events than the 50 mg dose. Only two thromboembolic events were reported, an embolism of the toe and a renal infarction, both occurred in persons in the 50 mg dose group. The 50 and 150 mg dose groups had significant increases (p = .0008; p = .027, respectively) in D-dimer concentrations, indicating lack of D-dimer suppression. The higher dose dabigatran etexilate and warfarin groups showed no significant decreases or increases in D-dimer concentration (Ezekowitz et al., 2007). In this study, higher doses of dabigatran etexilate were associated with increased incidence of major bleeding events, as well as greater suppression of D-dimer concentration. Thromboembolic events occurred only among participants receiving the lowest dose of dabigatran etexilate. The study was limited by its small sample size, short treatment duration, and lack of direct comparisons between dabigatran etexilate and warfarin. The potential for gender bias also existed because 81.9% of participants were male (Ezekowitz et al., 2007). Because aspirin has antiplatelet effects, concomitant use may have served as a confounding variable, interfering with the results (Tymkow, 2013).
RE-LY trial The RE-LY trial was a large, multicenter, phase III study directly comparing dabigatran etexilate to warfarin (Connolly et al., 2009) that ultimately led to FDA approval of the new anticoagulant agent and the new ACCF/AHA/HRS recommendations (Wann et al., 2011). By comparing dabigatran etexilate to warfarin, the researchers hoped to show that dabigatran etexilate was not inferior to warfarin as an oral anticoagulant for patients with AF (Ezekowitz et al., 2009). They used the same eligibility and exclusion criteria used in the PETRO study and planned to enroll at least 18,000 patients to achieve statistical power (Ezekowitz et al., 2007, 2009). Over a 24-month period, 18,113 patients from 951 clinical cen-
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ters in 44 countries participated; the average age of participants was 71 years; over half were male, and their average CHADS2 score was 2.1 (Connolly et al., 2009). Participants were randomly placed into one of three groups: blinded doses of 110 or 150 mg of dabigatran etexilate twice daily or a nonblinded dose of 1, 3, or 5 mg of warfarin adjusted for the INR goal of 2.0–3.0 (Connolly et al., 2009). While the PETRO study monitored coagulation values, the RE-LY trial determined results based on outcome events, specifically stroke, systemic embolism, and major hemorrhage. To prevent bias, two independent investigators reviewed documents to identify outcome events, using blinded review. This was important considering the risk of bias associated with the open-label warfarin control group (Connolly et al., 2009). Further efforts to increase validity included random assignment of treatment groups and control of possible confounding variables (Tymkow, 2013). To reduce the risk that a patient’s previous exposure to warfarin would influence study results, equal enrollment of the warfarin-experienced and the warfarin-na¨ıve was enforced (Connolly et al., 2009). Because this was a trial comparing dabigatran etexilate to warfarin (Connolly et al., 2009), the researchers needed to demonstrate that dabigatran etexilate was no worse than warfarin in a predetermined, clinically important amount (Polit & Beck, 2012). The researchers utilized Cox proportional hazards modeling and set the noninferiority margin at 1.46 based on previous placebo trials with warfarin. To prove noninferiority, the hazard ratio of dabigatran etexilate compared to warfarin needed to be less than 1.46 (p < .0125) based on a 97.5% confidence interval (CI; Ezekowitz et al., 2009). Relative risks (RRs), CI, and p values were determined by Cox regression, and medication discontinuation and adverse events were compared with chi-square tests (Connolly et al., 2009). The incidence of stroke and systemic embolism was significantly lower (p < .001) for participants receiving dabigatran etexilate doses of 110 or 150 mg than for persons receiving warfarin, demonstrating noninferiority. The 150 mg dose of dabigatran showed superiority to warfarin in the prevention of ischemic stroke (RR, 0.66; 95% CI, 0.53–0.82; p < .001). Hemorrhagic stroke was significantly lower in participants receiving either dose of dabigatran etexilate (p < .001) than in the warfarin group. The 110 mg dose was associated with a significantly lower incidence of bleeding (RR, 0.80; 95% CI, 0.69–0.93; p = .003), but the 150 mg dose was not (RR, 0.93; 95% CI, 0.81–1.07; p = .31). The 150 mg dose decreased the risk of ischemic stroke (p = .005), but was associated with increased risk for major bleeding in patients ࣙ 75 years of age. Dyspepsia was the only adverse effect
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significantly (p < .001) more prevalent in the dabigatran etexilate groups (Connolly et al., 2009). Overall, results from the RE-LY trial indicated that dabigatran etexilate is noninferior to warfarin and provided evidence that a 110 mg dose is associated with decreased incidence of major bleeding (Connolly et al., 2009). This was a more extensive study than the PETRO trial, with a larger sample from multiple centers in many countries, longer duration of treatment, and direct comparisons between dabigatran etexilate and warfarin. However, the potential that aspirin would serve as a confounding variable was not completely eliminated, because concomitant use was neither enforced nor prevented (Connolly et al., 2009). INR levels in the control group may also have influenced results, because INR levels were therapeutic only 64.2% of the time (Blommel & Blommel, 2011), and strict adherence to warfarin dose-adjustment algorithms was not enforced (Connolly et al., 2009).
Secondary analysis of RE-LY data Subgroup analysis of vitamin K antagonist experienced and vitamin K antagonist na¨ıve patients indicated that both populations had a significantly lower risk for ischemic stroke with the 150 mg dose of dabigatran etexilate than with warfarin (RR, 0.66; 95% CI, 0.49–0.89; p = .007 and RR, 0.63; 95% CI, 0.46–0.87; p = .005, respectively), indicating the benefit of switching patients on warfarin to dabigatran etexilate (Ezekowitz et al., 2010). A secondary analysis of the RE-LY data categorizing patients based on CHADS2 score indicated that the 150 mg dose of dabigatran etexilate was most beneficial for participants with the highest CHADS2 scores (Oldgren, Alings et al., 2011). Dabigatran etexilate has an approximate cost of $6.75– $8.00 per day, compared to a total yearly cost of $50 for warfarin (Wartak & Bartholomew, 2011). Freeman et al. (2011) examined data from the RE-LY trial to compare the cost-effectiveness of dabigatran etexilate to warfarin in a hypothesized population of patients 65 years old and older with AF and with a CHADS2 score ࣙ 1. Warfarin was compared to 110 and 150 mg twice daily doses of dabigatran etexilate to determine net cost over 35 years, or until death, and quality of life was compared based on risk for adverse events. While the total cost of 150 mg dabigatran etexilate ($168,398) exceeded the total cost of warfarin ($143,193), quality-adjusted life-years (QALYs) were higher with dabigatran etexilate (10.84) than with warfarin (10.28), indicating that dabigatran etexilate was more cost-effective. Dabigatran etexilate was more cost-effective than warfarin for patients at highest risk for ischemic and hemorrhagic stroke (Freeman et al., 2011). 194
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Postmarketing data on dabigatran etexilate Since FDA approval in October 2010, more than 3.5 million prescriptions of dabigatran etexilate have been dispensed, with approximately 725,000 patients receiving this medication from U.S. outpatient retail pharmacies (Food and Drug Administration [FDA], 2012). A higher than expected number of serious bleeding events among dabigatran etexilate users has been reported to the FDA Adverse Event Reporting System, resulting in further investigation of the safety of this anticoagulant (FDA, 2012; Southworth, Reichman, & Unger, 2013). The FDA conducted a review of actual GI and intracranial bleeding events using their Mini-Sentinel Database, which compares new users of dabigatran etexilate with new users of warfarin to determine if the reports received postmarketing represent true increased bleeding risk for dabigatran etexilate as compared to warfarin (FDA, 2012). After reviewing the data, the FDA found lower incidence rates of GI and intracranial hemorrhage among new users of dabigatran etexilate than among new users of warfarin and no recommended changes were made for the use of dabigatran etexilate (FDA, 2012; Southworth et al., 2013). Reasons for higher reported bleeding events considered by the FDA include greater likelihood of reporting a bleeding event with a novelty drug than with the long-used warfarin, failure of providers to make dosage adjustments for patients with impaired renal function, and different use of dabigatran etexilate postmarketing than in the RE-LY trial (FDA, 2012; Southworth et al., 2013). Recently released postmarketing analyses by the FDA of 134,000 Medicare patients, aged 65 or above, indicate that new users of dabigatran as compared to warfarin have a lower risk for embolic stroke, intracranial hemorrhage, and death (FDA, 2014). Additionally, the risk for MI was the same for users taking both drugs. However, a higher incidence of major GI bleeding was noted among dabigatran users as compared to warfarin. No new FDA recommendations were made for drug use or labeling (FDA, 2014). Berger, Salhanick, Chase, and Ganetsky (2013) conducted a prospective cohort chart review of emergency department patients presenting at an urban tertiary hospital with a hemorrhage while taking either dabigatran etexilate (n = 15) or warfarin (n = 123) during a 6-month period in 2011. The findings from this study indicated that GI hemorrhages were the most common bleeding event for both dabigatran etexilate (80%) and warfarin (48%) groups. Only patients receiving warfarin were found to have intracranial hemorrhages. Patients presenting with dabigatran etexilate related bleeding were older (77 vs. 70 years), had a shorter length of stay (3.5 vs. 6.0 days), and received fewer packed RBC transfusions (1.1 vs. 2.3 units)
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and fewer units of fresh frozen plasma (0.3 vs. 1.1 units) than those with warfarin-related bleeding. More than half (53%) of the group receiving dabigatran etexilate had suffered some kind of acute renal injury, defined as ࣙ 50% increase in serum creatinine level or ࣙ 0.3 mg/dL absolute increase in serum creatinine level, compared to 42% of those receiving warfarin. Additional trials have been conducted to study the efficacy and safety of dabigatran etexilate. The RE-ALIGN research trial evaluated the use of dabigatran etexilate in patients with AF and a mechanical heart valve (Van de Werf et al., 2012). However, the study was terminated early due to greater risk for stroke, MI, embolism, and bleeding events among patients receiving dabigatran etexilate than among those receiving warfarin. The FDA has since mandated that dabigatran etexilate is contraindicated for patients with a mechanical heart valve (FDA, 2013). The RE-DEEM trial evaluated the safety and efficacy of dabigatran etexilate when given with a dual antiplatelet treatment to patients who had a recent MI (Oldgren, Budaj et al., 2011). Dabigatran etexilate was associated with a reduction in coagulation activity but also with a dose-dependent increase in bleeding events. The net clinical benefit of dabigatran etexilate among patients with a recent MI could not be concluded (Oldgren, Budaj et al., 2011). The RE-MEDY and RE-SONATE trials compared the safety and efficacy of dabigatran etexilate with warfarin or placebo, respectively, in patients with a history of VTE (Schulman et al., 2013). In the RE-MEDY and RE-SONATE trials, dabigatran etexilate was found to be effective in the long-term treatment of VTE and noninferior to warfarin. However, in comparison to warfarin (RE-MEDY trial) but not placebo (RE-SONATE trial), patients receiving dabigatran etexilate had an increased incidence of MI, reasons for this finding are not clear (Schulman et al., 2013). Dabigatran etexilate has not been approved for the treatment of VTE (Blommel & Blommel, 2011).
Implications for practice This review provides evidence to assist nurse practitioners and other healthcare professionals to make an informed decision about the use of dabigatran etexilate for the management of nonvalvular AF. Dabigatran etexilate has been shown to be associated with a less complicated patient management regimen than warfarin. Frequent monitoring of INR is not required. There are fewer interacting drugs and foods, because the drug does not depend on the cytochrome P450 enzyme system for metabolism (Grave, 2012). Currently, the FDA recommends 150 mg of dabigatran etexilate twice daily unless creatinine clearance is 15–30 mL/min; for those patients,
75 mg twice daily is recommended, because the drug is excreted primarily unchanged by the kidneys (Blommel & Blommel, 2011). It is important to note that testing of the 75 mg dose was not reported in either the PETRO (Ezekowitz et al., 2007) or RE-LY (Connolly et al., 2009) trials. The FDA recommends that healthcare professionals reassess renal function during treatment, particularly with concomitant diuretic use, episodes of fluctuating renal function, or hypovolemia, and make necessary dose adjustments (FDA, 2012). As with warfarin, nurse practitioners should provide patients with written directions about when to seek immediate care for the development of the signs and symptoms of anticoagulant-associated bleeding (FDA, 2012). Unlike warfarin, dabigatran etexilate does not have a specific reversal agent for bleeding (Blommel & Blommel, 2011). The increased incidence of dyspepsia and twice-daily dosing requirements with dabigatran etexilate do raise the potential for medication nonadherence (Grave, 2012). However, with careful patient selection along with patient education, encouraging dedication to the medication regimen and reporting of adverse effects, dabigatran etexilate can be effectively used as a warfarin alternative. Because the drug is new and its associated long-term clinical course is not completely known, nurse practitioners should be on the lookout for further studies and FDA announcements.
Conclusion Significant evidence from the PETRO and RE-LY trials and postmarketing analyses of dabigatran etexilate indicate that this direct thrombin inhibitor is efficacious and a noninferior alternative to warfarin for the prevention of ischemic stroke in patients with nonvalvular AF who meet the ACCF/AHA/HRS criteria. Findings from the RE-LY trial indicate that twice daily dosing of 150 mg of dabigatran etexilate is superior to warfarin for the prevention of ischemic stroke and patients taking dabigatran etexilate suffer a lower incidence of intracranial hemorrhage than those taking warfarin (Connolly et al., 2009). Risk for dabigatran etexilate related GI bleeding appears to be higher than that for warfarin (FDA, 2014). The research conducted on dabigatran is sound, reliable, and has included samples representative of the population who should receive warfarin anticoagulation according to current guidelines (Wann et al., 2011). Findings from the aborted RE-ALIGN trial reinforce that dabigatran etexilate is contraindicated in those with prosthetic mechanical heart valves (Van de Werf et al., 2012) and it is currently not recommended for VTE prophylaxis or post-MI (Blommel & Blommel, 2011; Oldgren, Budaj et al., 2011; Schulman et al., 2013). 195
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