Stroke Prevention in Atrial Fibrillation: Focus on the role of a Pharmacist

Transcription

1 Stroke Prevention in Atrial Fibrillation: Focus on the role of a Pharmacist Author: Michelle Schymik, PharmD, BCPS PGY1 Residency Coordinator and Lead Pharmacist for Deaconess Hospital Evansville, IN Regional Coordinator for Butler University College of Pharmacy and Health Sciences Original article published by the Indiana Pharmacists Alliance (IPA). This activity may appear in other state pharmacy association journals. Reprinted with permission. Copyright 2012 Indiana Pharmacists Alliance. ACPE UPN: H04-P 1.5 Contact Hours (0.15 CEU s) This is a knowledge-based activity. See end of article for CE details. Target Audience: Pharmacists Faculty Disclosure: The faculty have no conflicts of interest to disclose. Goal: The goal of this lesson is to assess the risks of stroke in patients with atrial fibrillation and recommend appropriate stroke prevention based upon patient-specific parameters. Objectives: At the conclusion of this lesson, successful participants should be able to: 1. List the risk factors for stroke in atrial fibrillation patients 2. Determine a patient s level of stroke risk based upon at least one scoring method. 3. Recommend appropriate antithrombotic therapy based upon a patient s risk for stroke due to atrial fibrillation and other patientspecific parameters. INTRODUCTION Atrial fibrillation is the most common cardiac arrhythmia in the United States. This arrhythmia accounts for 34.5% of the hospitalizations for abnormal rhythm. There are currently over 2.2 million Americans diagnosed with atrial fibrillation, either paroxysmal or persistent. The incidence increases with age to the point that it occurs in approximately 8% of Americans over 80 years of age. The age-adjusted risk is higher in men and has increased over time. The age-adjusted risk is lower in African-Americans when compared to whites 1. DEFINITIONS Atrial fibrillation can be divided into two categories, valvular or non-valvular. The treatments will differ slightly by type of atrial fibrillation. The American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for management of atrial fibrillation define non-valvular atrial fibrillation as absence of rheumatic mitral stenosis, valve repair, or a prosthetic heart valve. The focus of this article will be in the patient with non-valvular, also known as non-rheumatic, atrial fibrillation and will be referred to simply as atrial fibrillation in the remainder of this document. The treatment options will be referred to as either antiplatelet, anticoagulant, or antithrombotic. Antiplatelet agents discussed in this article will include aspirin and clopidogrel. Anticoagulant therapy will include either warfarin or dabigatran. Finally, antithrombotic therapy is a broad term used to indicate any agent which helps prevent thrombosis and includes antiplatelet and anticoagulant agents. RISK FACTORS FOR STROKE The risk of ischemic stroke due to nonrheumatic atrial fibrillation is 5% per year, which is a 2 to 7-fold increase over those without this arrhythmia. Nearly half of the atrial fibrillation-associated strokes occur in those over the age of 75 years 1. The risk of stroke must be balanced with the risk of bleeding from pharmacologic therapy. A shift to identifying those at low risk for stroke from atrial fibrillation has occurred in an effort to only anticoagulate those patients who will truly benefit from therapy 2. Many risk factors have been identified as a potential cause for stroke. Several groups have performed systematic reviews to determine the risk of stroke related to atrial fibrillation, the Stroke in Atrial Fibrillation Working Group 3, UK National Institute for Health and Clinical Evidence (NICE) Group 4, Taiwan National Cohort Study, and Denmark Cohort Study 2. The identified risk factors for stroke and their corresponding relative risk are listed in Table 1 2. ASSESSMENT TOOLS FOR INDIVIDUAL STROKE RISK The assessment tools described are useful in quickly determining the risk of stroke from atrial fibrillation. The CHADS 2 score, found in Table 2, is the most widely used tool to assess the stroke risk in patients with atrial fibrillation. This assessment assigns a score for certain risk factors for stroke, such as congestive heart failure, hypertension, elderly age, diabetes, and prior stroke or transient ischemic attack Page 1

2 (TIA). It is weighted to assign one point for each risk factor except prior stroke/tia which received two points. Table 3 shows how the risk of stroke increases with every additional point in the CHADS 2 score 5. It has been suggested that the CHADS 2 score is limited in the fact that it does not consider every pertinent risk factor, such as gender and vascular disease and that it might underestimate the risk of stroke in some populations 2,5. In 2010, the European Society of Cardiology (ESC) recommended the use of CHA 2 DS 2 -VASc score to determine stroke risk in atrial fibrillation because it includes both major risk factors and the clinically relevant non-major risk factors for stroke in a weighted manner. Major risk factors are defined as prior stroke/tia/systemic emboli and age greater than or equal to 75 years. The other risk factors which would fall into the category of clinically relevant nonmajor risk factors include heart failure, hypertension, diabetes, vascular disease, age of years, and female gender. If a patient has two risks in the nonmajor risk factor category, oral anticoagulation therapy would be indicated 6. Table 2 compares the CHADS 2 assessment with CHA 2 DS 2 - VASc assessment. The CHA 2 DS 2 -VASc tool complements the initial assessment in patients with an initial CHADS 2 score of 0-1 to further evaluate all risk factors. With CHADS 2, the maximum score obtainable is 6 points. A maximum of 9 points can be calculated using the CHA 2 DS 2 -VASc assessment. Since dabigatran was not FDA-approved when these scales were created, the antithrombotic therapy initially recommended based upon these two assessment scales is no therapy, aspirin, or warfarin. The ESC supports the use of dabigatran in higher risk patients if the bleeding risk is moderate or low. This group also recommends use of dabigatran in patients with measurable bleeding risk, but at a lower dose of 110mg twice daily (which is not FDAapproved dosing in the United States) 6. In 2011, the American College of Cardiology Foundation, American Heart Association/Heart Rhythm Society (ACCF/AHA/HRS) supported the addition of dabigatran as an option for oral anticoagulation 7. Essentially, the CHA 2 DS 2 -VASc scale recommends an oral anticoagulant with the presence of one major risk factor or two clinically relevant non-major risk factors 6 ; while CHADS 2 scale requires a score of two (prior stroke/tia or two other risk factors) before oral anticoagulants are recommended 5. In cases when either oral anticoagulant or aspirin is recommended, the use of oral anticoagulant is preferred unless contraindicated. When either no therapy or aspirin is the recommended option, the use of no therapy is recommended to balance the benefit of therapy with bleeding risks 2. The 2006 ACC/AHA/ESC guidelines for management of patients with atrial fibrillation define another method to assign stroke risk. This assessment tool factors in even more risk factors for stroke when determining the stroke list. The risk factors are listed as high, moderate, or low and assignment of antithrombotic therapy is based upon number and type of risk factors. Table 4 lists the risk factors and severity assigned by this set of guidelines 1. These tools are quick references which help the clinician quickly assess the stroke risk of patients and determine appropriate evidence-based stroke prevention. PHARMACOLOGIC THERAPY FOR STROKE PREVENTION Once the patient s risk of stroke from atrial fibrillation has been assessed, Table 5 lists the recommended treatment based upon the risk factor assessment tool used 1. The recommended treatment balances the underlying risk of stroke with the pharmacologic agent s ability to decrease the stroke risk. It has been estimated that aspirin reduces the risk of stroke by approximately 22%. Warfarin has been shown to reduce the stroke risk by 64%, but this comes with a 69% higher bleeding risk when compared to placebo 9. In the Randomized Evaluation of Long-Term Anticoagulation (RE-LY) trial, dabigatran 150mg twice a day was proven superior to warfarin in preventing stroke or systemic emboli with a relative risk of 0.66, but the bleeding risk was similar 10. As a result of the varying degree of reduction in stroke risk, aspirin s primary role is in the low risk population. Anticoagulants are recommended in those at high risk of developing stroke. As stated earlier, dabigatran was not FDA-approved when most guidelines and assessment tools were developed. It has been supported by the European Society of Cardiology 11 and its role is defined by the ACCF/AHA/HRS 7 in their focused update on the management of patients with atrial fibrillation with an update on dabigatran in Aspirin Aspirin mg daily is an alternative antithrombotic in low risk patients or in those who have contraindications to oral anticoagulants 1. Overall, aspirin has a limited role in preventing stroke from atrial fibrillation and the evidence is not consistently favorable, as it is with warfarin 5. Aspirin s benefits include its over-the-counter status, low cost, and lack of required routine monitoring. If this is the risk-based pharmacologic choice, patients would need to be appropriately counseled to monitor for gastrointestinal bleeding and the benefit of taking this medication with food. Warfarin Warfarin is a vitamin K antagonist which requires approximately 5 days to achieve a therapeutic effect as measured by INR. Typical daily doses range from 2.5 to 7.5mg daily. The patient s response must be monitored by checking an INR at least monthly due to its unpredictable response. Since warfarin has been marketed since 1954, in depth detail about its dosing and drug interactions will not be discussed. Please refer to prescribing information for more detail when needed 12. Page 2

3 Determining the INR goal is the first step to beginning warfarin therapy. The INR goal for prevention of stroke due to atrial fibrillation is INR of for nearly all patients receiving warfarin. It was shown that an INR goal of has approximately 80% the efficacy as the goal range of To maximize the risk-to-benefit ratio, this lower goal of could be assigned to patients with high risk of bleeding and age greater than 75 years. Higher INR goals are also appropriate for some patients. If a patient experiences a stroke or systemic emboli while therapeutic (INR ) on warfarin for atrial fibrillation, the INR goal could be increased to the maximum target INR of instead of adding antiplatelet therapy 1,8. There are benefits associated with choosing warfarin as the anticoagulant to prevent stroke. First, the degree of anticoagulation can be monitored with a simple laboratory test. This test is also available in a point-of-care device. Warfarin can also be reversed if the INR is significantly elevated or if bleeding occurs. The acquisition cost of warfarin is low compared to dabigatran. Warfarin has proven efficacy in stroke prevention with decades of experience. Warfarin has a number of limitations which reduce its usefulness, including slow onset of therapeutic effect, monitoring requirements, narrow therapeutic range, common and potentially significant drug interactions, and food-drug interactions 12. The most troubling limitation is its unpredictable response. The response to warfarin is dependent on many factors including dietary interactions, herbal interactions, alcohol/smoking interactions, drug interactions, organ function, and metabolism. The prescribing information lists 11 exogenous factors, 47 drug class interactions, and 131 specific drug interactions which can increase the INR. There are almost as many factors which can decrease the INR. Full detail can be found in the prescribing information. Significant interactions involve the cytochrome P450 enzymes because the S-enantiomer of warfarin is metabolized by CYP2C9 and the R-enantiomer is metabolized by CYP3A4 and CYP1A2. The S-enantiomer is the more potent isomer and genetic variations in CYP2C9 can have significant impact on warfarin s effect 12. Most chronic interactions cause a change in warfarin dose based upon INR results. The most concerning interactions are acute, shortterm interactions because they often result in elevated INR. This is especially common when medications like metronidazole, sulfamethoxazoletrimethoprim, and fluconazole are started. The effect of warfarin is decreased with increased vitamin K intake through diet. This interaction can cause fluctuation in INR and patients should be counseled to maintain a consistent intake of vitamin K containing food each week. Another limitation is frequent monitoring of the INR and patients should not go longer than 4 weeks between visits. It has been suggested that results from randomized controlled trials might not be applicable in clinical practice due to difficulty achieving a therapeutic INR with same frequency as studies. One study reported that the INR time-in-range in real practice was 60%, but other studies typically have much lower percentages of time in therapeutic range 5. Warfarin monitoring adds direct cost to the low acquisition cost of obtaining the medication itself. Elderly patients often need assistance getting to appointments so transportation issues surrounding INR monitoring presents another limitation to warfarin therapy. The question of holding warfarin for a procedure in atrial fibrillation patients was first addressed in the 2006 ACC/AHA/ESC guidelines 8. The consensus of the 2006 writing group for the management of atrial fibrillation supported the interruption of warfarin for up to 1 week in patients without a mechanical valve who will undergo a procedure having a risk of bleeding without requiring bridge therapy. In high-risk patients or those requiring longer than 1 week interruption, unfractionated heparin or low-molecular weight heparin bridge therapy is recommended 8. All patients should be counseled when warfarin is initiated. The counseling should include written material to reinforce the information and a review of the following topics: mechanism of action in patient-friendly language, role of warfarin in preventing stroke from atrial fibrillation, signs of a stroke, anticipated duration of use, INR goal, importance of INR testing, frequency of INR testing, proper administration, tablet color, plan if a dose is missed, signs of bleeding and management at home, drug interaction overview (prescription, OTC, and herbal medications), dietary consistency with vitamin K, risks with pregnancy, when to call physician, handling emergencies or bleeding events, and carrying an emergency alert bracelet or medication list. Dabigatran Dabigatran is the first oral direct thrombin inhibitor approved by the FDA and it is indicated to prevent stroke and systemic emboli from non-valvular atrial fibrillation. The only direct comparison of warfarin and dabigatran was the noninferiority RE-LY trial. The RE-LY trial compared warfarin to dabigatran 150mg twice daily and dabigatran 110mg twice daily. The results showed that dabigatran 110mg twice daily had a similar risk of stroke and systemic emboli as warfarin, but a lower rate of major hemorrhage. Dabigatran 150mg twice daily resulted in a statistically significant decrease in the risk of stroke and systemic emboli when compared to warfarin (1.11% per year vs. 1.69% per year, respectively) and had similar rates of major bleeding (3.11% vs. 3.36%, respectively). Dabigatran 150mg twice daily was associated with a lower rate of hemorrhagic stroke when compared to warfarin (0.38% vs. 0.1%, respectively) 20. Since only the 150mg twice daily dosing of dabigatran is approved in the United States, dabigatran use can be associated with a lower rate of stroke when compared to warfarin, but does not result in less bleeding. Page 3

4 Per FDA approval, dabigatran is dosed at 150mg orally twice daily, but a dosage reduction to 75mg twice daily is required when the creatinine clearance (CrCl) is 15-30ml/min. Dabigatran does not have dosing recommendations in patients with CrCl<15ml/min or those receiving dialysis. If a patient misses a dose, the dose should be taken as soon as it is remembered and at least 6 hours before the next dose is due. Doses should never be doubled to make up for a missed dose 13. Dabigatran, due to its moisture sensitivity, must be stored in the original bottle which contains a desiccant in the lid. It cannot be transferred to pillboxes or other containers. Once the bottle is opened, the date should be written on the bottle and dabigatran must be used within 60 days. Patients should be educated not to break, chew, or open the capsules as this could potentially result in a 75% increase in the bioavailability of the medication 13. The most common adverse reactions leading to discontinuation of dabigatran were bleeding and gastrointestinal events. The gastrointestinal events included dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea 13. The duration of dabigatran s effects are based upon creatinine clearance. Converting from dabigatran to warfarin is fairly complex and the details of this conversion are listed in Table 6. It should be noted that dabigatran can contribute to an elevated INR for up to two days after it is discontinued. Warfarin can be converted safely to dabigatran when the INR is less than 2.0. Creatinine clearance also plays a role in holding dabigatran before a procedure. If CrCl >50ml/min, dabigatran should be held 1-2 days before an invasive procedure. It should be held 3-4 days before a procedure if the CrCl <50ml/min 13. The advantages of dabigatran include lack of required laboratory monitoring and very few drug interactions since it does not undergo extensive cytochrome P450 metabolism 13. Dabigatran is not significantly metabolized by the cytochrome P450 system, but it is removed by p-glycoprotein. Dronedarone increases the concentration of dabigatran by times and prescribing information suggests decreasing the dose of dabigatran to 75mg twice daily when given with dronedarone to patients with CrCl of 30-50ml/min. Dabigatran should also be avoided with rifampin since it induces p- glycoprotein 13. P-glycoprotein inhibitors, such as amiodarone, verapamil, quinidine, or clarithromycin, only need to be avoided with dabigatran patient s CrCl is less than 30ml/min. Systemic ketoconazole s p-glycoprotein inhibition required that dabigatran dose be decreased to 75mg twice daily when the patient s CrCl is 30-50ml/min due to their ability to inhibit p-glycoprotein. Dabigatran requires an acidic environment to be absorbed, but no dosage adjustments are needed with proton pump inhibitors 13. Amiodarone increases dabigatran concentrations by 60%, but also causes an increased renal clearance. The combination of these two effects causes no alteration of dabigatran concentration and no dosage adjustment is warranted. Despite changes in pharmacokinetics with verapamil based upon timing of administration and type of product used, there are no dosage changes required when verapamil is prescribed with dabigatran 21. Dabigatran s limitations include a lack of a reversal agent, lack of clinical trial outcome data in patients with CrCl<30ml/min, and potentially increased bleeding in patients over age of 75 years. In safety data from the RE- LY trial, there appears to be an increased risk for extracranial bleeding with dabigatran 150mg twice daily in patients over 75 years of age. When viewing the data by age subgroups (<75 years vs. >75 years), the risk of major bleeding of any type and extracranial bleeding is statistically significantly higher for dabigatran 150mg twice daily when compared to dabigatran 110mg twice daily and warfarin for patients greater than or equal to 75 years of age.. To put this into perspective, the risk of extracranial bleeding for patients of 75 years of age or older was 3.44%, 4.10%, and 4.68% for warfarin, dabigatran 100mg twice daily, and dabigatran 150mg twice daily, respectively. This data is being used to support the need for the addition of the 110mg twice daily dose by the FDA and to stress the risk of bleeding in those over 75 years of age. Dabigatran 150mg twice daily had a statistically significant lower risk of hemorrhagic stroke when compared to warfarin with rates of 0.1% and 0.38% 14. Rivaroxaban Rivaroxaban is an oral direct factor Xa inhibitor which was approved in November 2011 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This medication is dosed 20mg daily with evening meal, but the dose is decreased to 15mg daily with evening meal when the CrCl is 15-50ml/min. Rivaroxaban should be avoided when CrCl is less than 15ml/min. Timing is important when changing to or from rivaroxaban. A patient can be switched from warfarin to rivaroxaban as soon as the INR is less than 3 to prevent periods of inadequate anticoagulation. Rivaroxaban does cause in increase in INR so INR values during co-administration of rivaroxaban and warfarin may be of limited clinical value. If patients are switched from rivaroxaban to warfarin, the warfarin should be started when rivaroxaban is stopped and parenteral anticoagulant bridge therapy is recommended 15. Rivaroxaban is a substrate of p- glycoprotein, CYP3A4, CYP2J2, and ATP-binding cassette G2 transporters. Concomitant use should be avoided with combined strong p-glycoprotein and CYP3A4 inhibitors (ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) and avoided with combined strong p-glycoprotein and CYP3A4 inducers (carbamazepine, phenytoin, rifampin, and St. John s wort). Several drug interactions with CYP3A4 inhibitors (erythromycin, clarithromycin, and fluconazole) and inducers are less serious and the risk versus benefit must be evaluated 15. Page 4

5 This medication was approved by the FDA based upon the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) 16 study. This randomized, double-blind noninferiority trial of 14,264 patients compared rivaroxaban 20mg daily (dose decreased to 15mg daily when CrCl=30-49ml/min) to warfarin (INR goal 2-3) to determine the effect on preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation. The outcomes demonstrated that rivaroxaban is non-inferior to warfarin at preventing stroke and systemic emboli with a primary endpoint rate of 1.7% and 2.2% per year, respectively. The rate of major and non-major bleeding was statistically similar between the two treatment arms with a rate of 14.9% for rivaroxaban and 14.5% for warfarin. The rivaroxaban did have statistically fewer intracranial hemorrhages (0.5% vs. 0.7%) and fewer fatal bleeds (0.2% vs. 0.5%) when compared to warfarin 16. There was a higher incidence of stroke when patients were transitioned off rivaroxaban to warfarin after completion of the study. During the 28 days following the study, stroke occurred in 22 patients transitioned from rivaroxaban to open-label warfarin and in 6 patients transitioned from warfarin study medication to open-label warfarin. Since there was no overlap in therapy during the transition from rivaroxaban, it was suspected that the increased stroke rate was due to inadequate anticoagulation before attaining a therapeutic INR. This data resulted in a black box warning for increased risk of thrombotic events with discontinuation of rivaroxaban and recommends use of another anticoagulant if therapy must be interrupted 15. The ROCKET-AF trial studies patients at higher risk of stroke than those in other study populations. Patients were required to have a CHADS 2 score of two to meet inclusion criteria, but the average CHADS 2 score was This is higher than the average CHADS 2 score of in RE-LY trial 10. The biggest concern with ROCKET-AF results is that rivaroxaban was proven non-inferior to warfarin therapy which was less than optimal. The patients in the warfarin group experienced mean time in the therapeutic range of only 55%, which is much lower than the results from recent anticoagulation trials with a mean of 64-68% of the time in therapeutic range 15. Rivaroxaban has an advantage over warfarin since it does not require routine monitoring and has more predictable dosing. Rivaroxaban must be held at least 24 hours before a procedure which is another advantage of this therapy. The medication may have to be held longer in presence of renal insufficiency due to prolonged half-life 15. The limitations of rivaroxaban are similar to dabigatran in that it has no specific reversal agent, but the prescribing information states that prothrombin complex concentrate or recombinant factor VIIa may be considered. Also, rivaroxaban cannot be used in severe renal impairment (CrCl<15ml/min) or in patients with hepatic impairment (Child-Pugh B and C) 15. Combinations with antiplatelet therapy The 2011 focused update for atrial fibrillation management specifically covers the combination of aspirin and anticoagulants and the combination of aspirin and clopidogrel 17. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) trial 18 compared clopidogrel (75mg daily) plus aspirin (75-100mg daily) with warfarin (INR goal ) to prevent vascular events in patients with atrial fibrillation and one or more risk factors for stroke. The primary outcome event was defined as stroke, systemic emboli, myocardial infarction, or vascular death. This study was stopped early due to evidence of warfarin s superiority. The event rate was 3.93% for warfarin versus 5.60% for antiplatelet therapy. There was no difference in major hemorrhages, but there was significantly more minor bleeding in the clopidogrel plus aspirin arm. The authors concluded that warfarin therapy was superior to the combination of clopidogrel plus aspirin in this population. Another trial involving clopidogrel was the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-A) trial 19. This trial compared aspirin to aspirin plus clopidogrel in patients who had atrial fibrillation, but were not candidates for warfarin. The primary outcome was stroke, myocardial infarction, systemic emboli, or death from vascular cause. This trial was continued for 3.6 years and found that the rate of major vascular events was 6.8% for aspirin plus clopidogrel versus 7.6% for aspirin. This statistically significant difference resulted in a relative risk of 0.89 with aspirin plus clopidogrel and the difference stemmed from a decrease in stroke. There was more major bleeding in the aspirin plus clopidogrel arm (2% per year compared to 1.3% per year for aspirin alone). The 2011 ACCF/AHA/HRS guidelines for management of atrial fibrillation added a new recommendation that aspirin plus clopidogrel might be considered for those who are unsuitable for warfarin to reduce the risk of stroke 17. No randomized trials have compared outcomes when aspirin, clopidogrel, and warfarin are combined in high risk patients with two or more conditions, such as atrial fibrillation, mechanical prosthetic value, or drug-eluting stent. It is known that the risk of bleeding is higher with this triple therapy 17. PHARMACIST S ROLE The Pharmacist s expertise can be used to solve the new dilemma of choosing between warfarin and dabigatran in patients at intermediate or high risk of stroke from atrial fibrillation. There are several areas to consider when helping make this decision. Page 5

6 The following areas should be factored into the decision to use warfarin or dabigatran in patients whose stroke risks requires use of one of these anticoagulants: Valvular Atrial Fibrillation Valvular atrial fibrillation was not the focus of this analysis, but warfarin remains the treatment for this population. The 2011 ACCF/AHA/HRS focused update on management of patients with atrial fibrillation (update on dabigatran) points out that the RE-LY trial excluded patients with prosthetic heart valves and hemodynamically significant valvular heart disease. The guidelines state that dabigatran is a useful alternative to warfarin in patients who do not have prosthetic heart valves, hemodynamically significant valvular heart disease, severe renal failure defined as CrCl<15ml/min, or advanced liver disease defined as impaired baseline clotting function 7. Medication Compliance and Administration When deciding between warfarin and dabigatran, medication adherence is one factor. Both medications require the patient to be compliant for effective therapy, but dabigatran requires twice daily dosing and may be a burden which might decrease efficacy for some patients. This may be further complicated by the fact that dabigatran cannot be placed in a pillbox. Warfarin requires more time to return to a therapeutic INR after missed doses so frequent or consecutive missed warfarin doses could result in multiple days of subtherapeutic INR results. Rivaroxaban is once daily dosing, but does require administration with food. Dabigatran capsules cannot be opened or crushed so patients must be able to swallow the entire capsule for this medication to be an acceptable alternative. Risk of Bleeding All three anticoagulants, dabigatran, rivaroxaban, and warfarin, are associated with an increased risk of bleeding. The only direct comparison of dabigatran and warfarin is found in the RE-LY trial which demonstrated a major bleeding rate of 3.36% per year in the warfarin group and 3.11% in the dabigatran 150mg twice daily group (p=0.31). Additional benefit was noted with dabigatran for the rate of hemorrhagic stroke which occurred 0.38% per year with warfarin and 0.10% per year with dabigatran 150mg twice daily (p<0.001) 10. The sub-analysis of the RE- LY trial is questioning the additional risk of major and extracranial bleeding in patients over 75 years of age when prescribed dabigatran 14. A direct comparison for rivaroxaban and warfarin was consulted in ROCKET-AF trial. Both medications had similar bleeding rates for major and non-major bleeding. Rivaroxaban did have a statistically lower risk of intracranial bleeding and fatal bleeding. The European Society of Cardiology uses HAS-BLED to assess bleeding risks and the role of dabigatran versus warfarin. The HAS-BLED scale, listed in Table 7, assigns one point for each of the following: hypertension, abnormal renal or liver function (1 point each), stroke, bleeding, labile INR, elderly (age over 65 years), and drugs or alcohol use (1 point each) 20. When determining which medication to use, a HAS-BLED score of 0-2 suggested warfarin or dabigatran can be used safely. If the HAS-BLED score is >3, then a lower dose of dabigatran is suggested. However, this lower dose of dabigatran 110mg twice daily is not approved for use in the United States. This higher risk category should have anticoagulation initiated with caution and have regular follow-up. The HEMORR 2 HAGES scale was derived from patients taking anticoagulants for atrial fibrillation and was used to determine the risk of bleeding in this study population. The clinical prediction rule gives one point for hepatic or renal disease, ethanol abuse, malignancy, old age defined as age>75 years, reduced platelet count, prior bleeding (which is assigned 2 points), uncontrolled hypertension, anemia, genetic factors, excessive fall risk, or stroke. The details of point assignment and rate of bleeding from the HEMORR 2 HAGES assessment are found in Table Major bleeding would require supportive care with dabigatran, rivaroxaban, or warfarin. There is no reversal agent for dabigatran (half-life is hours) or for rivaroxaban (half life is 5 to 9 hours). Warfarin can be reversed with vitamin K, fresh frozen plasma, prothrombin complex concentrate, or factor VIIa depending on the urgency of reversal need. Acceptability of Other Side Effects During the RE-LY trial, the rates of adverse reactions leading to discontinuation were 21% for dabigatran and 16% for warfarin 13. Since dabigatran has a higher incidence of dyspepsia and also had a non-significant trend toward increased risk of myocardial infarction (MI), 9 these adverse effects could aid in determining which patients should use dabigatran as second line. Since the relative risk of developing MI was 1.38 (warfarin MI rate of 0.53% per year vs. dabigatran 150mg twice daily rate of 0.74%) 10, this could play a role in determining therapy. Prescribers should note that the incidence of MI was less than 1% for both groups so it is not clear if this should influence prescribing. Rivaroxaban s primary adverse reaction is bleeding complications. Some adverse reactions were reported in postmarketing data, such as agranulocytosis, anaphylaxis, and hepatobiliary complications. It is difficult to assess the frequency of these events due to voluntary reporting 15. Warfarin has unique adverse reactions which need to be considered. Purple toe syndrome results from microembolization of cholesterol emboli after disruption of atherotic plaques. This syndrome can occur during weeks 3-10 of therapy and the site of embolization can include toes, visceral Page 6

7 organs (kidney, pancreas, spleen, or liver), spinal cord, or any other area of the body. This syndrome can progress to gangrene. Tissue necrosis can also result in patients with deficiencies in the body s natural anticoagulants, Protein C and Protein S 12. Onset of Action Dabigatran has an onset of therapeutic effect within 2 to 4 hours of administration 13. Peak rivaroxaban levels are noted at 2 to 4 hours 15. The onset of therapeutic effect for rivaroxaban is In contrast, warfarin typically requires a minimum of five days to achieve therapeutic INR values 12. This may cause use of additional bridge therapy with heparin or low molecular weight heparin which raises the overall cost of therapy. This can be a problem for patients who do not have prescription insurance to cover the cost of the bridge therapy or those who fear injection medication at home. Predictability of dosing Both dabigatran and rivaroxaban have predictable dosing which requires a dosage adjustment for renal insufficiency Warfarin dosing is not predictable and the prescribing information only specifies that dosing must be individualized 12. Food and Drug Interactions Dabigatran is not metabolized by cytochrome P450 enzymes; however, interactions with the small number of p- glycoprotein inhibitors or inducers may limit the use of this medication to prevent stroke. Rivaroxaban is metabolized by p- glycoprotein and cytochrome P450 enzymes. A small list of combined strong CYP3A4 and g-glycoprotein inhibitors/inducers should be avoided concomitantly 15. Warfarin might not be ideal for patients with unpredictable or excessive alcohol use, frequently changing amount of tobacco use, frequently changing cytochrome P450 interactions, or unpredictable dietary vitamin K intake. Stable interactions tend to cause less of a problem with warfarin therapy. Renal Insufficiency The RE-LY study excluded patients with CrCl less than 30ml/min and patients with liver disease 10. As a result, dabigatran dosing for impaired renal function is based upon pre-clinical data. The approved prescribing information for dabigatran in the United States and Canada differ based upon the interpretation of data from the RE-LY study. In the United States, dabigatran dose for CrCl of 15-30ml/min is 75mg twice daily and the medication has no dosing recommendations when CrCl is less than 15ml/min or in dialysis patients. Prescribing information in Canada lists dabigatran as contraindicated when CrCl is less than 30ml/min 21, which is most likely based upon the fact that patients were excluded from RE-LY if CrCl was less than 30ml/min. Rivaroxaban has dosage adjustments for CrCl of 15-50ml/min. It should be avoided when CrCl is less than 15ml/min 15. Since no dosage adjustments are needed for warfarin in renal insufficiency 12, warfarin would be required for patients with CrCl less than 15ml/min, but may be beneficial in those with CrCl less than 30ml/min. Hepatic Insufficiency No dosage adjustments are required for dabigatran in hepatic insufficiency 13. Rivaroxaban is avoided in Child Pugh Class B or C 15. In contrast, hepatic dysfunction can potentiate the effects of warfarin 12 and a dosage reduction and increased monitoring would be warranted. Monitoring Warfarin requires monitoring of the INR at least monthly and this can pose a challenge for some patients. Patients may be noncompliant with INR monitoring due to a range of problems from transportation issues to cost of monitoring 12. The ACCF/AHA/HRS and the FDA have concluded that patients who have excellent INR control may have little to gain by switching to dabigatran due to its twice daily dosing and greater risk of nonhemorrhagic side effects 7,23. Dabigatran and rivaroxaban do not require routine monitoring. Cost and Insurance Coverage A cost-effective analysis was conducted using costs from the insurance payer s perspective. The analysis included inpatient and outpatient medical costs, as well as, prescription costs over the course of 20 years. The annual cost of warfarin therapy was $545 when factoring in prescription costs and the Medicare reimbursement for 14 INR tests with a low-level office visit. The annual cost of dabigatran was $3240 and incorporated only prescription drug costs. The authors concluded that dabigatran was cost-effective for patients at high risk of hemorrhage or high risk of stroke unless INR control with warfarin was excellent (INR in range >72.6% of the time). The authors also concluded that warfarin is cost-effective in moderate-risk atrial fibrillation unless INR control was poor 9. Incorporating data into practice This analysis has proven that there are many factors to consider when determining the best antithrombotic agent to prevent stroke in a patient with atrial fibrillation. When the clinician must decide between oral anticoagulants, Table 9 lists suggested characteristics from the analysis which might favor either dabigatran or warfarin. The clinician must balance the risk of stroke and the bleeding risk from antithrombotic therapy using the tools provided in this article. The Alabama Pharmacy Association Research and Education Foundation (APAREF) is accredited by the Accreditation Council for Pharmacy Page 7

8 Education (ACPE) as a provider of continuing pharmacy education. To receive continuing pharmacy education (CPE) credit, pharmacists MUST COMPLETE QUIZ AND EVALUATION FORM and mail to APA at 1211 Carmichael Way, Montgomery, AL A score of 80% or above is required to receive CPE credit. This is a free service to APA members. Non-members must include a processing fee of $20 per quiz. Initial Release Date: 11/12/12. Expiration Date: 12/31/14. Questions: Call APA at (334) References 1. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Heuzey J-Y, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;57:e Lip GYH. Stroke risk assessment in atrial fibrillation: an update. Article from the e-journal of the ESC Council for Cardiology Practice. Available from uncils/ccp/ejournal/volume9/pages/stroke-riskassesment-in-atrial-fibrillation-anupdate-gregory-lip.aspx. Accessed August 19, Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69(6): Hughes M, Lip GY. Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb Haemost 2008; 99: Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:546S-592S. 6. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19): Wann LS, Curtis AB, Ellenbogen KA, Estes NAM 3rd, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, writing on behalf of the 2006 ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation Writing Committee ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm 2011;8:e1 e8. 8. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey J-Y, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc J-J, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Circulation. 2006;114: Published online before print August 2, DOI: 10/1161/CIRCULATIONAHA Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 2011; 123: Connolly SJ, Ezekowitz MD, Phil CBD. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation. The task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31: Bristol-Myers Squibb, Inc. Coumadin (warfarin sodium) prescribing information, Available from Accessed August 26, Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate) prescribing information, November Available from Accessed December 27, Brooks, M. Time to revisit dabigatran dose in the United States? Available from Accessed September 4, Janssen Pharmaceuticals, Inc. Xarelto (rivaroxaban) prescribing information, Available from files/pdf/xarelto_0.pdf#zoom=100. Accessed December 28, Patel MR, Mahaffy KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10): Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, writing on behalf of the 2006 ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation Writing Committee ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123: Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367: Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360: Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial Page 8

9 fibrillation: the HAS BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol. 2011;57: Hunchuck JE, Lake JD. Dabigatran for stroke prevention in all patients with atrial fibrillation? Pharmacotherapy 2011;31(8): Bounameaux H, Perrier A. Duration of anticoagulation therapy for venous thromboembolism. Hematology. 2008;1: U.S. Food and Drug Administration. Boehringer Ingelheim advisory committee briefing document: dabigatran etexilate. Available from y Committees/CommitteesMeetingMateria ls/drugs/cardiovascularandrenaldrugs AdvisoryCommittee/UCM pdf. Accessed August 18, Page 9

10 TABLE 1: Risk factors for stroke in non-valvular atrial fibrillation and the associated degree of risk Risk Factor Degree of Risk RR=relative risk. OR=odds ratio, HR=hazard ratio Identified by Stroke in AF Working Group Previous stroke or transient ischemic attack RR = 2.5 Age RR = 1.5 per decade Hypertension RR = 2.0 Diabetes RR = 1.8 Female gender RR = 1.6 Identified by the Taiwan Nationwide Cohort Study Age Hypertension OR = Diabetes OR = Heart Failure OR = Previous stroke or transient ischemic attack OR = Peripheral arterial disease (PAD) OR = Identified by Denmark Cohort Study Vascular disease (prior MI or PAD) OR = (age yrs vs yrs) OR = (age>75yrs vs. age<65 yrs) HR = 2.04 at 5 years Table 2 TABLE 2: Stroke risk assessment CHADS 2 and CHA 2 DS 2 -VASc Risk Factor CHADS 2 Score CHA 2 DS 2 -VASc Score Congestive Heart Failure/LV dysfunction (EF<40%) 1 1 Hypertension (history of HTN or SBP>160) 1 1 Age greater than or equal to 75 years 1 2 Diabetes 1 1 Prior Stroke or TIA 2 2 (includes thromboembolism in CHA 2 DS 2 -VASc) Vascular Disease 1 (Prior MI, peripheral arterial disease, aortic plaque) Age years 1 Sex (female gender) 1 TABLE 3: Risk of stroke based upon CHADS 2 score CHADS 2 Score Adjusted Stroke Rate per 100 person years (with 95% confidence interval) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Page 10

11 TABLE 4: Risk factors for stroke as assigned by the 2011 ACC/AHA/ECS guidelines for management of patients with atrial fibrillation and recommended therapy High Risk Factors Moderate Risk Factors Weak Risk Factors Prior stroke, TIA, or embolus Mitral valve disease Prosthetic heart valve Hypertension Heart Failure LV dysfunction (EF<35%) Age greater than or equal to 75 years Diabetes mellitus Age years Female CAD Thyrotoxicosis Risk Category Antithrombotic Therapy Recommended No risk factors Aspirin mg daily One moderate risk factor Aspirin mg daily or Warfarin (INR goal of ) Any high risk factor or Warfarin (INR goal of ) more than 1 moderate risk factor TABLE 5: Recommended antithrombotic therapy based upon risk assessment tools CHADS 2 CHA 2 DS 2 -VASc Risk determined by 2006 Recommended Anticoagulation Therapy Score Score guidelines in Table 4. >2 >2 Any high risk factor >2 moderate risk factors Oral Anticoagulant Therapy [Warfarin or Dabigatran or Rivaroxaban] moderate risk factor Any weak risk factor 0 0 No risk factors (aspirin recommended and no therapy is not an option) Oral Anticoagulant Therapy (preferred) [Warfarin or Dabigatran or Rivaroxaban] or Aspirin mg No therapy (preferred) or Aspirin mg TABLE 6: Converting from dabigatran to warfarin Creatinine Clearance When to Start Warfarin CrCl >50ml/min Start warfarin 3 days before discontinuing dabigatran CrCl 30-50ml/min Start warfarin 2 days before discontinuing dabigatran CrCl 15-30ml/min Start warfarin 1 day before discontinuing dabigatran CrCl <15 ml/min No recommendation Page 11

12 TABLE 7: HAS-BLED bleeding risk scoring system Letter Clinical Characteristic Points H Hypertension (SBP>160mmHg) 1 A Abnormal renal or liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding (history of bleeding or predisposed to bleeding) 1 L Labile INR s (therapeutic <60% of time) 1 E Elderly (age over 65 years) 1 D Drugs (antiplatelet agents, NSAIDS) or alcohol (1 point each) 1 or 2 TABLE 8: Rates of major bleeding from HEMORR 2 HAGES clinical prediction rule Letter Clinical Characteristic Points H E Hepatic (cirrhosis, AST/ALT 2xnormal, albumin<3.6g/dl) Renal insufficiency (CrCl<30ml/min) Ethanol (h/o alcohol abuse, alcohol related hospitalization, or worsening alcoholic liver disease) 1 1 M Metastatic cancer 1 O Older age (age over 75 years) 1 R Reduced platelet count (plt< 75,000) or function, scheduled use of aspirin 1 or NSAID R Re-bleeding 2 H Hypertension (uncontrolled with SBP>160) 1 A Anemia (Hct<30 or Hgb<10g/dl) 1 G Genetic factors (CYP2C9*2 and/or CYP2C9*3 ) 1 E Elevated fall risk (includes Alzheimer's dementia, Parkinson's disease, schizophrenia) S Stroke (prior ischemic stroke) 1 1 HEMORR 2 HAGES Score Rate of major bleeding per 100 patient-years with warfarin > Page 12

13 TABLE 9: Characteristics which might aid in determining which anticoagulant to use to prevent stroke in atrial fibrillation Factor Favors Dabigatran or Rivaroxaban Favors Warfarin Valvular atrial fibrillation Compliance or Administration Risk of Bleeding Patient Past Medical History Onset of action Predictability of dosing Drug Interactions Renal function Hepatic Function Monitoring Cost and Insurance Coverage Rivaroxaban is dosed daily Dabigatran decreases hemorrhagic stroke Rivaroxaban decreased intracranial and fatal bleeding Protein C or S deficiency Onset is hours and predictable Dabigatran and rivaroxaban have specific dosing recommendations Dabigatran has few interactions and few medications to avoid Rivaroxaban has fewer interactions than warfarin, but several medications must be avoided Avoid warfarin in hepatic insufficiency No routine testing required Better if transportation issues Better when cannot afford additional cost of testing Patients with prosthetic heart valve Patients with hemodynamically significant valvular disease Dabigatran is dosed BID and cannot be placed in pillbox Dabigatran must be swallowed whole Rivaroxaban must be with food Warfarin can be reversed h/o GERD, peptic ulcer disease High risk of MI (questionable limitation to dabigatran) Dabigatran o 75mg BID if CrCl=15-30ml/min o Avoid if CrCl<15ml/min Rivaroxaban o 15mg daily if CrCl=15-50ml/min o Avoid if CrCl<15ml/min Warfarin still preferred for patients with excellent INR results (i.e. INR in range >72.6% of the time) Lower annual cost even when factoring in INR monitoring Lower prescription cost for patients with no prescription insurance Page 13