Kamal, Ayeesha Kamran

Kamran, Syed Habibullah

Muzammil, Syeda Maria

English

eCommons@AKU

eCommons@AKUDepartment of Medicine Department of MedicineJanuary 2013What are the new therapeutic alternatives towarfarin in atrial fibrillation?Syed Habibullah KamranAga Khan UniversityAyeesha Kamran KamalAgha Khan University, ayeesha.kamal@aku.eduSyeda Maria MuzammilAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_med_medPart of the Neurology CommonsRecommended CitationKamran, S. H., Kamal, A., Muzammil, S. M. (2013). What are the new therapeutic alternatives to warfarin in atrial fibrillation?. JPMA.The Journal of the Pakistan Medical Association, 63(1), 129-130.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_med/363Why are the studies on these newer agentsimportant? Atrial fibrillation is associated with an increased risk ofstroke (mean= 4.5% per year) and hence necessitatesstarting the patients on lifelong oral anticoagulants.Vitamin K Antagonists, like Warfarin, have been themainstay of treatment, but remain grossly underusedbecause of increased bleeding risk, variability in resultsand the need for therapeutic monitoring. The advent ofnewer agents like Dabigatran, direct factor IIa (thrombin)inhibitor and Apixaban and Rivaroxaban, Factor Xainhibitors may make this a little easier. These fast acting,short lived, fixed dosed (unmonitored) agents exhibitlimited drug and food interactions and provide consistentand predictable anticoagulation.The Randomised Evaluation of Long-TermAnticoagulation Therapy (RE-LY) trial evaluated theefficacy and safety of two doses of Dabigatran relative toWarfarin in patients with atrial fibrillation. TheRivaroxaban versus Warfarin in Nonvalvular AtrialFibrillation (ROCKET AF) trial compared the outcomes ofRivaroxaban (20 mg /day) and dose adjusted Warfarin.Apixaban (2.5 mg BID) was also compared with aspirin(81-324 mg QD) for stroke prevention in AF ApixabanVersus Acetylsalicylic Acid to Prevent Strokes(AVERROES) trial. This review highlights the main findings in these threetrials and presents a brief comparison of the efficacy ofWarfarin against Dabigatran, Apixaban and Rivaroxaban. Who were the study participants?RE-LYenrolled and followed 18,113 elderly patients (meanage: 71.6 ± 8.7 years) from 44 countries in the 2-yearlargest ever randomized controlled trial of antithrombotictherapy. Subjects had a mean CHADS2 2.1 ± 1.1 and apartfrom atrial fibrillation had one other stroke predisposingrisk factor : (previous stroke or TIA, left ventricular ejectionfraction < 40%, New York Heart Association heart failureclassification of II or higher, age > 75 years, or age 65-74years plus diabetes mellitus, hypertension, or coronaryartery disease). History of stroke within 14 days or a severeone in past 6 months, increased bleeding risk, active liverdiseases, creatinine clearance < 30mL/min were some ofthe exclusion criteria. The ROCKET AF trial enrolled 14,264 patients (meanCHADS2>3.5) with non valvular atrial fibrillation and 55%of them were positive for a history of stroke, TIA orsystemic embolism at the start of the study (median time707 days). The AVERROES trial recruited 5, 599 subjects (mean age 70years) non valvular atrial fibrillation patients in whomVitamin K antagonists were contraindicated and they hada mean CHADS2 of 2. 86% did not have a previous strokeor TIA.What was the intervention?In RE-LY trial, out of 18,113study participants 6,022wererandomly assigned to either receive adjusted-doseWarfarin, with INR target 2.0 to 3.0, monitored monthly.6,015 subjects were administered Dabigatran 110 mg BIDand 6,076 received Dabigatran 150 mg BID. Thecategorization employed double blinding.In ROCKET AF trial, 14,264 patients with non valvular atrialfibrillation were either administered Rivaroxaban (20mg/dL) or dose-adjusted warfarin (target INR 2.0-3.0). In the AVERROES trial, subjects were randomly assigned toreceive 5mg Apixaban BID or a lower dose 2.5 mg BID ifthe patient had age > 80 years, weight < 60 kg or serumcreatinine > 1.5 mg/dL. Doses of Aspirin administeredwere 81 mg (64%), 162 mg (27%), 243 mg (2%) or 324 mg(7%). Study participants were noted for occurrence ofischaemic or haemorrhagic events and systemicembolism. Study subjects had a mean CHADS2 ? 2 with 14% positive for a history of prior stroke.What were the findings?Study participants were noted for primary end point i.e.ischaemic/haemorrhagic stroke and systemic embolism.Dabigatran, 150 mg BID and 110 mg BID, exhibited lesserincidence of stroke and systemic embolism (1.11% /yearand 1.53% /year) compared to warfarin (1.69%/year). Netclinical benefit showed higher RR 7.09% per year forWarfarin and Dabigatran 110 mg compared to 6.91% perVol. 63, No.1, January 2013129Evidence Based MedicineWhat are the new therapeutic alternatives to warfarin in atrial fibrillation?Syed Habibullah Kamran,1 Syeda Maria Muzammil,2 Ayeesha Kamran Kamal31,3Stroke Program, Neurology Section, Department of Medicine, 2MedicalCollege, Aga Khan University, Karachi, Pakistan.Correspondence: Ayeesha Kamran Kamal. Email: ayeesha.kamal@aku.eduyearfor Dabigatran 150 mg. Mortality with Dabigatran 150mg BID (3.64% year) was lowest overall when comparedto warfarin (4.13% per year; RR, 0.88; 95% CI,0.80-1.03)and Dabigatran 110 mg BID (3.75%; RR,0.91; 95% CI, 0.80-1.03). However, major bleeding was lowest (2.71 % peryear) with Dabigatran 110mg BID compared to Warfarin(3.36 % per year) and Dabigatran 150 (3.11 % per year). The ROCKET AF trial showed that 14.9% of patients peryear in the Rivaroxaban group and 14.5% in thewarfaringroupwere complicated with non-major and majorclinical bleeds. Rivaroxaban administration was alsoassociated with net benefiti.e. an overall primary endpoint incidence of 2.5 % compared to Warfarin (3.61 %) insubjects with history of prior stroke, TIA or systemicembolism. AVERROES trial attested to the superiority of Apixabanover Aspirin therapy with incidence of stroke or systemicembolism 1.67 % and 3.7 % per year. Net clinical benefit ofApixaban was 5.3% per year and that of Aspirin was 7.2%per year. In patients who had previously taken Vitamin Kantagonist, Apixaban was more effective in preventingstroke or systemic embolism, the incidence being 1.4 % asopposed to 4.2 % per year for Aspirin. What were the conclusions? These agents were comparable in efficacy overall andbetter in safety profile in patients without renal failurecompared to warfarin, albeit at high cost.Based on thetrials some newer international recommendations (AHAguidelines) emerged and are hence noteworthy. Warfarin(1A), Dabigatran (1B), Apixaban (1B) and Rivaroxaban (IIaB) were all indicated for stroke prevention in patients withnon valvular atrial fibrillation. How does this affect clinical practice inPakistan?These agents are certainly useful in selected populations.It must be remembered that missing a dose equates withbeing non anticoagulated due to the shorter half-life ofthese agents. The safety of combining Dabigatran,Rivaroxaban, or Apixaban with an antiplatelet agent hasnot been established. Reversal also is of concern inbleeding scenarios. Use of Factor VII, cryoprecipitate oremergency dialysis has been proposed. Cost will be asignificant barrier in resource poor areas; although studiesmay reveal that they may be eventually cost effective dueto less money spent on tests, anticoagulation clinicsavoiding strokes and bleeds. These studies must beperformed locally before these medicines can be widelyrecommended regionally. Acknowledgements and Disclosures: There are no relevant conflicts of interest to declare withregards to this review.Recommended Reading: 1. Wallentin L, et al. Efficacy and safety of dabigatrancompared with warfarin at different levels of internationalnormalised ratio control for stroke prevention in atrialfibrillation: an analysis of the RE-LY trial. Lancet 2010; 376:975-83.2. Hankey GJ, et al. Rivaroxaban compared with warfarin in patientswith atrial fibrillation and previous stroke or transient ischaemicattack: a subgroup analysis of ROCKET AF. Lancet Neurol 2012; 11:315-22.3. Ahrens, I., G.Y. Lip, and K. Peter, What do the RE-LY, AVERROES andROCKET-AF trials tell us for stroke prevention in atrial fibrillation?Thromb Haemost 2011; 105: 574-8.J Pak Med Assoc130 S. H. Kamran, S. M. Muzammil, A. K. Kamal

What are the new therapeutic alternatives to warfarin in atrial fibrillation?

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What are the new therapeutic alternatives to warfarin in atrial fibrillation?

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