New Oral Anticoagulants for Atrial Fibrillation
2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.112.099283
ISSN1524-4539
AutoresSarah A. Spinler, Valerie Shafir,
Tópico(s)Venous Thromboembolism Diagnosis and Management
ResumoHomeCirculationVol. 126, No. 1New Oral Anticoagulants for Atrial Fibrillation Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBNew Oral Anticoagulants for Atrial Fibrillation Sarah A. Spinler, PharmD, FCCP, FASHP, FAHA, AACC, BCPS (AQ Cardiology) and Valerie Shafir, PharmD, BCPS Sarah A. SpinlerSarah A. Spinler From the Department of Pharmacy Practice and Pharmacy Administration, University of the Sciences in Philadelphia, Philadelphia College of Pharmacy, Philadelphia, PA. and Valerie ShafirValerie Shafir From the Department of Pharmacy Practice and Pharmacy Administration, University of the Sciences in Philadelphia, Philadelphia College of Pharmacy, Philadelphia, PA. Originally published3 Jul 2012https://doi.org/10.1161/CIRCULATIONAHA.112.099283Circulation. 2012;126:133–137IntroductionCase 1A: A 68-year-old man with a past medical history of atrial fibrillation (AF), hypertension, and type 2 diabetes mellitus has been on anticoagulation therapy with warfarin for 6 years. The patient's target international normalized ratio (INR) is 2.0 to 3.0. The patient has been managed by a pharmacist-run anticoagulation clinic, and his recent warfarin doses and INR values are shown inTable 1. He has had no bleeding or thrombotic complications. His current medications include warfarin, metformin, lisinopril, and atorvastatin. The patient has recently read about the United States Food and Drug Administration (FDA) approvals of dabigatran etexilate and rivaroxaban and would like to know if he should be switched from warfarin to dabigatran.Table 1. INR Values for Patient in Case 1aDateINRWarfarin Dose5/1/122.47.5 mg6/2/122.57.5 mg6/30/121.77.5 mg7/14/123.17.5 mg7/27/12 (today)2.87.5 mgCase 1B: After discussion with the cardiologist and pharmacist, the patient in Case 1A decided that he would like to switch to dabigatran etexilate. He and his referring cardiologist would like to know how to switch a patient from warfarin to dabigatran. Pertinent labs include a serum creatinine of 0.7 mg/dL (creatinine clearance 80 mL/min) and liver function tests within normal limits. His medications remain unchanged.Case 2: A 70-year-old, 70-kg woman with a past medical history of hypertension presented to the emergency department with signs and symptoms of acute heart failure. She was diagnosed with new-onset AF and rapid ventricular response. After successful rate control with a β-blocker and anticoagulation with heparin, she underwent successful cardioversion after a transesophageal echocardiogram demonstrating no thrombi or valvular heart disease with an ejection fraction of 70%. Her other medications include ramipril and hydrochlorothiazide. Based on her CHADS2 score of 2 (hypertension and heart failure) and CHA2DS2-VASC score of 3 (hypertension, age 65–75 years, and female sex) a decision is made to anticoagulate the patient with one of the new oral anticoagulants. Pertinent laboratory tests include an INR of 1.0, liver function tests within the normal range, serum creatinine of 1.4 mg/dL, and a therapeutic aPTT of 70 seconds. What are drug selection considerations between dabigatran etexilate and rivaroxaban?Dabigatran Etexilate and Rivaroxaban for Stroke Prevention in Atrial FibrillationDabigatran etexilate (Pradaxa) is a prodrug that is rapidly converted to the active direct thrombin (factor IIa) inhibitor dabigatran. Dabigatran etexilate 150 mg orally twice daily was approved by the FDA on October 19, 2010 for marketing in the United States for the prevention of stroke and systemic embolism in patients with nonvalvular AF.1 The FDA approval of dabigatran came after the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. The RE-LY trial was a large, open-label, randomized trial in which dabigatran was compared with warfarin (goal INR 2.0–3.0) in 18 113 patients with nonvalvular AF. Rates for the primary outcome of all stroke (ischemic or hemorrhagic) or systemic embolism were 1.71% per year in the warfarin group.2,3 Dabigatran 150 mg twice daily reduced the rate by 34% (from 1.71% per year with warfarin to 1.11% per year with dabigatran; P<0.001 for superiority intention-to-treat analysis; relative risk [RR], 0.65; 95% confidence interval [CI], 0.52–0.81), and at this dose there was no increase in major bleeding. The rate of nonhemorrhagic stroke was also significantly lower with 150 mg of dabigatran than with warfarin (0.92% versus 1.20%; RR, 0.76; 95% CI, 0.60–0.98) as was the rate of hemorrhagic stroke (0.10% versus 0.38%; RR, 0.26; 95% CI, 0.14–0.49). The frequency of dyspepsia was increased in patients receiving dabigatran (11.3% in the 150-mg group) as compared with warfarin (5.8%) and contributed to the greater second-year rate of dropout with dabigatran (≈21%) than with warfarin (16.6%).2,3Dabigatran is primarily cleared from the body renally (80%) and is a substrate of the efflux transporter P-glycoprotein (P-gp).1 Patients with creatinine clearance 75 years of age and those with creatinine clearance <50 mL/min. Dabigatran should not be administered to patients with acute kidney injury.1Table 2. Potential Drug Interactions With New Oral Anticoagulants Dabigatran Etexilate and Rivaroxaban*1,4,5CYP3A4†P-Glycoprotein (P-gp)InducerInhibitorStrong‡ModerateStrongModerateInducerInhibitor§CarbamazepineBosentanClarithromycin‖AmprenavirCarbamazepineAmiodaronePhenytoinEfavirenzConivaptan‖AprepitantPhenytoinConivaptan‖RifampinEtravirineGrapefruit juice(high-dose, double strength)AtazanavirRifampinClarithromycin‖St. John's wortModafenilIndinavir‖CiprofloxacinTiprinavir/RitonavirCyclosporineNafcillinItraconazole‖Darunavir/ RitonavirSt. John's wortDronedarone¶Ketoconazole‖DiltiazemErythromycinLopinivir/ Ritonavir‖ErythromycinIndinavir/Ritonavir‖NefazadoneFluconazoleLopinavir/ Ritonavir‖NelfinavirFosamprenavirItraconazole‖PosaconazoleGrapefruit juice(low-dose-single strength)Ketoconazole‖¶Ritonavir‖ImatinibQuinidineSaquinavirVerapamilRitonavir‖TelaprevirVerapamilTelithromycinVoriconazole*As determined by the FDA as of July 28, 2011.4†Interactions pertinent to rivaroxaban only.5‡Strong CYP3A4 inducers and P-gp inducers should be avoided with rivaroxaban.5§Avoid P-gp inhibitors with dabigatran etexilate in patients with creatinine clearance 15 to 30 mL/min.1‖Strong CYP3A4 inhibitors and P-gp inhibitors are contraindicated with rivaroxaban.5¶A dose reduction of dabigatran to 75 mg twice daily orally is suggested in patients with creatinine clearance 30 to 50 mL/min.1On July 1, 2011, the FDA approved rivaroxaban (Xarelto) 20 mg orally once daily for stroke prevention in AF based on the results of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET AF).5 ROCKET AF was a large, double-blind, randomized trial comparing rivaroxaban 20 mg once daily or a reduced dose of 15 mg once daily for patients with creatinine clearance of 30 to 49 mL/min with warfarin (goal INR 2.0–3.0) in 14 264 patients with nonvalvular AF. Rates for the primary outcome of all stroke (ischemic or hemorrhagic) or systemic embolism were 1.71% per year in the rivaroxaban group and 2.2% per year in the warfarin group (per-protocol as-treated analysis, probability value for noninferiority <0.001).6 There was no difference in major bleeding (3.6% per year with rivaroxaban versus 3.4% with warfarin (hazard ratio [HR], 1.04; 95% CI, 0.90–1.20). The rate of ischemic stroke was similar in the rivaroxaban-treated patients compared with warfarin-treated patients (1.34% versus 1.42%; HR, 0.94; 95% CI, 0.75–1.17), but there was a lower frequency of hemorrhagic stroke (0.26% versus 0.44%; HR, 0.59; 95% CI, 0.37–0.93) in the safety on-treatment study population. Study drug was discontinued for adverse events in 15% of both treatment groups.6Approximately 51% of an oral dose of rivaroxaban is metabolized primarily by CYP 3A4/5 and 36% renally eliminated as unchanged drug.6 It is a substrate of the efflux transporters P-gp and breast cancer resistance protein. The area under the plasma concentration time curve and maximum concentration of rivaroxaban are increased significantly after administration with food, and it is recommended that both the 15-mg and 20-mg tablets (but not the 10-mg tablet) be administered with the largest meal of the day, typically the evening meal.5 Product labeling recommends to avoid concomitant use of drugs which are both a strong P-gp inhibitor or inducer as well as a strong CYP3A4 inhibitor or inducer.5 Examples may be found inTable 2.1,4,5 Rivaroxaban should not be administered to patients with creatinine clearance <15 mL/min, and a dose reduction to 15 mg once daily is recommended for patients with AF and creatinine clearance 15 to 50 mL/min.5 Although not studied in ROCKET AF, pharmacokinetic modeling data and a single study in otherwise healthy patients with chronic kidney disease and creatinine clearance of 15 to 29 mL/min suggest that a 15-mg once-daily dose would result in rivaroxaban concentrations similar to those of patients with creatinine clearance ≥30 mL/min taking a 20-mg once-daily dose.5 Baseline serum creatinine should be measured and creatinine clearance calculated before starting rivaroxaban. Serum creatinine should be monitored periodically for patients with creatinine clearance near the cut points for dose adjustment (50 mL/min) or avoidance (15 mL/min). As with dabigatran, rivaroxaban should be avoided in patients with acute kidney injury.5Guidelines for Stroke Prevention in Atrial FibrillationThe 2011 American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society (ACCF/AHA/HRSA) Practice Guidelines recommend dabigatran as a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization.7 The guideline states that candidates for dabigatran should be without a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL/min), or advanced liver disease. More recently, the 2012 American College of Chest Physicians (ACCP) practice guidelines were released and they recommend anticoagulation over no anticoagulation or antiplatelet therapy for patients with a CHADS2 score of ≥1.8 The ACCP guidelines also recommend anticoagulation with dabigatran over anticoagulation with a vitamin K antagonist (Grade 2B recommendation). Neither guideline includes recommendations regarding rivaroxaban, because rivaroxaban was not yet approved by the FDA at the time of their writing.Influence of Quality of INR Control on Warfarin on Decision to Change Anticoagulant TherapyThe use of time in the therapeutic range (TTR) has become a recognized method to measure the effectiveness of warfarin. A strong relationship exists between TTR and bleeding or thromboembolic rates.9 An increased TTR has been associated with decreased mortality, myocardial infarction, stroke, and major bleeding.10 TTR can be determined by a variety of methods, and one of the most commonly used is Rosendaal's linear interpolation method. This method assumes that a linear relationship exists between 2 INR values and allocates a specific INR value to each day between tests for each patient.9,11The RE-LY investigators conducted a prespecified assessment of the primary and secondary outcomes of the RE-LY trial in relation to the quality of INR control.12 In RE-LY, study centers were given a warfarin dosing nomogram and suggested patient follow-up schedule for out-of-range INRs. The trial assessed the quality of warfarin treatment by calculating the individual TTR for individual patients by the Rosendaal method. The investigators then calculated the center's mean TTR (cTTR) for each individual center as an average of all individual TTRs in the warfarin group in each center. They used the average TTR each clinical center achieved in its patients treated with warfarin as an approximation of quality of INR control for all its patients receiving warfarin. The 4 TTR quartiles used in the trial were 72.6%. There were no significant probability values for an interaction between outcome and TTR.12The analysis found that the dabigatran 150 mg and 110 mg doses maintained their superiority and inferiority, respectively, versus warfarin regardless of cTTR.12 Rates of intracranial bleeding were lower at both doses of dabigatran than in the warfarin group, regardless of cTTR. For the dabigatran 150-mg dose, there were fewer major bleeding events in the dabigatran-treated patients than in the warfarin-treated patients in the lower TTR quartiles and no differences in the higher TTR quartiles. The risk of major gastrointestinal bleeding was higher in the dabigatran 150-mg group in the 2 highest quartiles of cTTR. The composite of all cardiovascular events and total mortality was reduced in the dabigatran 150-mg group at low cTTRs, but dabigatran and warfarin groups had similar rates at high cTTRs.12 A cost-effectiveness analysis of dabigatran for stroke prophylaxis in AF found that dabigatran 150 mg had no advantage (RR for major bleed, 1.16; RR for stroke, 1.21) to warfarin managed at medical centers where the INR control was in the highest quartile (>72.6% TTR).13In ROCKET AF, a blinded study, centers were not given warfarin dosing nomograms or suggestions on when to follow-up out-of-range INRs. In the safety, on-treatment population of ROCKET AF, the median cTTR was 58% with a median of 65% in the North American cohort. An analysis of cTTR and outcome between rivaroxaban and warfarin revealed no quartiles in which warfarin was superior to rivaroxaban and no significant interaction between cTTR and outcomes.14Case 1A ConclusionThe 68-year-old patient has an individual TTR of 75% when calculated using Rosendaal's linear interpolation method. This patient would be in the highest quartile of TTR in the RE-LY trial INR analysis.12 One must note that, although the RE-LY investigators focused on cTTR versus iTRR in their trial, the decision of whether to switch a patient from dabigatran to warfarin would be an individual patient-level decision. The use of cTTR is a surrogate for INR control and might not truly reflect TTRs for individual patients.15 The RE-LY INR analysis data suggest that the advantages of dabigatran are greater at centers with poor INR control than at those with good INR control. The 2011 ACCF/AHA/HRS guidelines state that "patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran."7 There is no precise definition of what constitutes excellent control. For this patient, we would recommend that the patient remain on warfarin unless he makes a personal decision to switch to dabigatran after discussing the risks and benefits.Case 1B ConclusionRecommendations for converting between anticoagulants, commonly referred to as bridging, based on product labeling for dabigatran and rivaroxaban are described inTable 3. The patient should discontinue warfarin. His CHADS2 score is 2, and his current INR is 2.8. He should have a baseline serum creatinine measured and creatinine clearance calculated. He is taking no medications which interact with dabigatran. Warfarin should be discontinued today and the INR measured in 3 days (missing 2 doses). Dabigatran should be started when the INR is <2.0. Patient information on dabigatran, which should be shared by the prescriber and pharmacist and the patient, has been published previously (notably, storage requirements have changed since this publication and currently state the product must be used within 4 months once opened versus the previous recommendation of 60 days).16Table 3. Recommendations for Converting Between Anticoagulants1,4From parenteral anticoagulation to dabigatran or rivaroxaban Heparin - Administer first dose at time heparin is discontinued LMWH - Administer first dose at time next dose is dueTo parenteral anticoagulation from Dabigatran For CrCl ≥30 mL/min wait 12 hours after last dose dabigatran For CrCl <30 mL/min, wait 24 hours after last dose of dabigatran Rivaroxaban At time of next scheduled rivaroxaban doseFrom warfarin to Dabigatran - Start dabigatran when INR<2.0 Rivaroxaban - Start rivaroxaban when INR<3.0From dabigatran to warfarin For CrCl ≥50 mL/min - Start warfarin 3 d before discontinuing dabigatran For CrCl 30–50 mL/min - Start warfarin 2 d before discontinuing dabigatran For CrCl 15–30 mL/min - Start warfarin 1 d before discontinuing dabigatranFrom rivaroxaban to warfarin Use parenteral anticoagulation bridgeLMWH indicates low-molecular weight heparin; CrCl, creatinine clearance; and INR, international normalized ratio.Case 2 ConclusionDecisions on which of the new oral anticoagulants to select are made on an individual patient basis. Differences exist between the agents in terms of dosing in renal impairment, frequency of administration, drug interactions, and, potentially, patient health insurance copays. This patient's estimated creatinine clearance by the Cockcroft Gault formula is 41 mL/min. If rivaroxaban is selected, she would require a reduced dose of 15 mg daily. Dabigatran may be administered at the usual dose of 150 mg twice daily. She is currently taking no medications which interact with either dabigatran or rivaroxaban. If she were taking a 3A4 inhibitor that is also not a P-gp inhibitor, we would recommend either dabigatran or warfarin over rivaroxaban, because renal dysfunction plus a 3A4 inhibitor may place the patient at higher risk for bleeding.4 The patient should be assessed for potential medication adherence problems. Gastrointestinal upset is common with dabigatran, and the patient should be told to report problems early if starting dabigatran and the regimen changed to rivaroxaban if necessary. The patient's food intake should be reviewed if selecting rivaroxaban, because it requires administration with a full meal. Because of her chronic kidney disease, we would recommend serum creatinine measurement at least every 6 months while she is taking either dabigatran or rivaroxaban and reassessment of her dose. If she is hospitalized with an acute illness, such as a recurrence of heart failure, we recommend cessation of oral anticoagulation and replacement with an injectable anticoagulation until her renal function can be assessed as stable. If the decision was made to reinitiate dabigatran or rivaroxaban, the heparin infusion should be discontinued at the same time as administration of either agent. Finally, the patient's pharmacy and insurance company should be contacted to identify the patient's copay and required prior authorizations needed so that the patient does not encounter financial difficulties which would impair adherence when initiating therapy.DisclosuresDr Spinler serves as a consultant to Janssen Pharmaceuticals, Inc.FootnotesCorrespondence to Sarah A. Spinler, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 S. 43rd St, Philadelphia, PA 19104. E-mail s.[email protected]eduReferences1. Pradaxa (dabigatran etexilate capsules) prescribing information. Boehringer Ingelheim Pharmaceuticals Inc; Ridgefield, CT: January2012. Google Scholar2. Connolly SJ, Ezekowitz MD, Yusef S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lews BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. 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Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010; 376:975–983.CrossrefMedlineGoogle Scholar13. Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation. 2011; 123:2562–2570.LinkGoogle Scholar14. Xarelto FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM270796.pdf. Accessed February 9, 2012. Google Scholar15. Lane DA, Lip GY. Quality of anticoagulation control in atrial fibrillation. Lancet. 2010; 376:935–937.CrossrefMedlineGoogle Scholar16. Spinler SA, Willey VJ. A patient's guide to taking dabigatran etexilate. Circulation. 2011; 124:e209–e211. 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July 3, 2012Vol 126, Issue 1 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.112.099283PMID: 22753535 Originally publishedJuly 3, 2012 Keywordspharmacologycoagulationdabigatrananticoagulantsrivaroxabanatrial fibrillationPDF download Advertisement SubjectsAnticoagulantsArrhythmiasCerebrovascular Disease/StrokePharmacologyPrimary Prevention
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