Implementation of NICE TAs 249, 256 and 275. Dabigatran, Rivaroxaban and Apixaban

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1 NHS Crby Clinical Cmmissining Grup Kettering General Hspital NHS Trust NHS Nene Clinical Cmmissining Grup Nrthamptn General Hspital NHS Trust Nrthamptnshire Healthcare Fundatin Trust Implementatin f NICE TAs 249, 256 and 275 Dabigatran, Rivarxaban and Apixaban fr the preventin f strke and systemic emblism in atrial fibrillatin April

2 Cntents Executive summary Page 3 1. Intrductin Page 4 2. The new ral anticagulants licensed fr strke preventin in AF Page 5 3. Guidance aims and chice f new OAC Page 8 4. Selectin f apprpriate patients Page Pathway fr initiatin Page Shared Care Guidance Page 15 Appendix 1 Page 16 Letter t Primary Care fllwing initiatin f Dabigatran fr Strke Preventin in AF Appendix 2 Page18 Letter t Primary Care fllwing initiatin f Rivarxaban fr Strke Preventin in AF Appendix 3 Page 20 Letter t Primary Care fllwing initiatin f Apixaban fr Strke Preventin in AF Guidance authrs Dr Matthew Lytteltn, Cnsultant Haematlgist, Kettering General Hspital Dr Karyn Lngmuir, Cnsultant Haematlgist, Kettering General Hspital Sue Smith, Head f Prescribing and Medicines Management, Nene and Crby Clinical Cmmissining Grups, Nrthamptnshire With cntributins frm - Dr Suchitra Krishnamurthy, Cnsultant Haematlgist, NGH Strke & Care f the Elderly Cnsultants, Cardilgists NGH Sctt Savage, Chief Pharmacist, KGH Dr Jnathan Shribman, GP and primary care East Midlands Cardivascular Netwrk representative Dr Yassir Javaid, GP Nrthamptn Junie, Gupta, Frmulary Pharmacist, NGH Prfessr Tm Rbinsn, Strke Lead, East Midlands Cardivascular Netwrk Dr Richard Andrews, Cardiac Lead, East Midlands Cardivascular Netwrk Bayer Behringer Ingelheim Apprved by - Nrthamptnshire Prescribing Advisry Grup April 2013 Review date June 2014 (Revisin f riginal versin apprved March 2012) - 2 -

3 Executive summary NICE has issued single Technlgy Appraisals fr dabigatran (Pradaxa ), fr rivarxaban (Xarelt ) and fr apixaban (Eliquis ) fr the preventin f strke and systemic emblism in atrial fibrillatin (TAs 249, 256 and 275). This guidance has been prduced t help identify thse patients wh are mst likely t benefit frm dabigatran, rivarxaban r apixaban fr this indicatin and t prvide advice n using these new drugs in the safest pssible manner. The guidance des nt and shuld nt ver-ride the NICE TAs. A clinician may chse t initiate dabigatran, rivarxaban r apixaban fr any patient within the Technlgy Appraisals criteria if clinically apprpriate. Dabigatran, rivarxaban and apixaban are rally active antithrmbtic agents. Dabigatran is a direct thrmbin inhibitr and rivarxaban and apixaban are ral direct factr Xa inhibitrs. They will be referred t as the NOACs (New Oral Anti- Cagulants) thrughut this dcument. The NOACs have the ptential advantage ver warfarin f nt requiring INR bld mnitring, but ther factrs abut the NOACs need t be taken int cnsideratin when deciding whether ne f the drugs is apprpriate fr an individual patient. These factrs include Unknwn lng term safety prfile f the NOACs. All 3 are black triangle drugs. Lack f reversibility f the NOACs. Cnsideratin f the patient s current INR cntrl n warfarin. Renal functin. Bleeding risk, especially GI bleeding risk. Drug interactins Cmpliance. The chice f NOAC is the decisin f the prescriber and there are prs and cns t each agent. Guidance is prvided bth fr patients newly diagnsed with AF and fr existing patients currently taking warfarin. In Nrthamptnshire it is recmmended that the NOACs shuld be initiated nly by a secndary care cnsultant (haematlgist, cardilgist r strke physician as apprpriate) with the supprt f their anticagulant clinics. Prescribing can then be passed t the GP with shared care advice (amber 2 status). This pathway fr initiatin will be reviewed nce experience with these new drugs becmes mre established. Warfarin remains a suitable first-line ral anticagulant fr mst patients

4 1. Intrductin NICE issued a Technlgy Appraisal (TA 249) Dabigatran etexilate fr the preventin f strke and systemic emblism in atrial fibrillatin in March Dabigatran etexilate is recmmended as an ptin fr the preventin f strke and systemic emblism within its licensed indicatin, that is, in peple with nnvalvular atrial fibrillatin with ne r mre f the fllwing risk factrs: previus strke, transient ischaemic attack r systemic emblism left ventricular ejectin fractin belw 40% symptmatic heart failure f New Yrk Heart Assciatin (NYHA) class 2 r abve age 75 years r lder age 65 years r lder with ne f the fllwing: diabetes mellitus, crnary artery disease r hypertensin. 1.2 The decisin abut whether t start treatment with dabigatran etexilate shuld be made after an infrmed discussin between the clinician and the persn abut the risks and benefits f dabigatran etexilate cmpared with warfarin. Fr peple wh are taking warfarin, the ptential risks and benefits f switching t dabigatran etexilate shuld be cnsidered in light f their level f internatinal nrmalised rati (INR) cntrl. NICE issued a Technlgy Appraisal (TA 256) Rivarxaban fr the preventin f strke and systemic emblism in atrial fibrillatin in May Rivarxaban is recmmended as an ptin fr the preventin f strke and systemic emblism within its licensed indicatin, that is, in peple with nnvalvular atrial fibrillatin with ne r mre risk factrs such as: cngestive heart failure hypertensin age 75 years r lder diabetes mellitus, prir strke r transient ischaemic attack. 1.2 The decisin abut whether t start treatment with rivarxaban shuld be made after an infrmed discussin between the clinician and the persn abut the risks and benefits f rivarxaban cmpared with warfarin. Fr peple wh are taking warfarin, the ptential risks and benefits f switching t rivarxaban shuld be cnsidered in light f their level f internatinal nrmalised rati (INR) cntrl

5 NICE issued a Technlgy Appraisal (TA 275) Apixaban fr the preventin f strke and systemic emblism in atrial fibrillatin in February Apixaban is recmmended as an ptin fr preventing strke and systemic emblism within its marketing authrisatin, that is, in peple with nnvalvular atrial fibrillatin with 1 r mre risk factrs such as: prir strke r ischaemic attack age 75 years r lder hypertensin diabetes mellitus symptmatic heart failure. 1.2 The decisin abut whether t start treatment with apixaban shuld be made after an infrmed discussin between the clinician and the persn abut the risks and benefits f apixaban cmpared with warfarin, dabigatran etexilate and rivarxaban. Fr peple wh are taking warfarin, the ptential risks and benefits f switching t apixaban shuld be cnsidered in light f their level f internatinal nrmalised rati (INR) cntrl. 2. The new ral anticagulants licensed fr strke preventin in AF 2.1 Dabigatran Dabigatran (mre crrectly called dabigatran etexilate a prdrug f dabigatran) is an rally active antithrmbtic agent. It is a direct thrmbin inhibitr, which has the ptential advantage ver warfarin f nt requiring bld mnitring, and may have fewer clinically imprtant drug interactins. The RE-LY study was a Phase III clinical study which evaluated the nn-inferirity f tw dses f dabigatran cmpared with warfarin in peple with AF wh were at mderate t high risk f strke. The primary efficacy endpint f the trial was incidence f strke (including haemrrhagic) and systemic emblism. The primary safety endpint was majr bleeding. The study fund that the lwer dse f dabigatran (110mg bd) was nn-inferir t warfarin at reducing the risk f strke and systemic emblism in peple with AF (RR 0.91; 95% CI 0.74 t 1.11; p<0.001 fr nn-inferirity). The higher dse (150mg bd) was fund t be statistically significantly mre effective than warfarin (RR 0.66; 95%CI 0.53 t 0.82; P<0.001; NNT172 ver ne year). The mean rates fr majr bleeding were 2.71% per year fr lw dse dabigatran, 3.11% per year fr high dse dabigatran and 3.36%/year fr warfarin. Whereas lwdse dabigatran was assciated with a reduced risk f majr bleeding (P=0.003; NNT 154 ver ne year), there were n significant differences between the high-dse dabigatran and warfarin in this respect

6 Dabigatran has thus demnstrated superirity t warfarin in preventing strkes, particularly haemrrhagic strkes, in peple with AF wh are at mderate r high risk f strkes. This finding, taken tgether with n greater risk f majr bleeding, suggests a pssible rle as an alternative t warfarin in such patients. 2.2 Rivarxaban Rivarxaban is an ral direct factr Xa inhibitr administered as a fixed-dse that des nt require labratry mnitring and, unlike warfarin, has n knwn fd and few drug interactins. The ROCKET AF study was a randmized, duble blind, duble dummy, sham INR trial which cmpared rivarxaban with warfarin. In this study, the per-prtcl, as treated primary analysis was designed t determine whether rivarxaban was nn-inferir t dse adjusted warfarin (target INR f ) in preventing strke r systemic emblism amng patients with nn-valvular atrial fibrillatin. Over a median 590 days f treatment expsure in the per-prtcl treatment grup, the event rates fr strke and systemic emblism were 1.7% per year in the rivarxaban daily grup and 2.2% per year in the warfarin grup (HR 0.79; 95% CI 0.66 t 0.96; p< fr nn-inferirity) In the intentin t treat (ITT) ppulatin as part f sensitivity analysis, the event rate fr strke and systemic emblism was 2.1% per year fr rivarxaban and 2.4% per year fr warfarin (HR 0.88; 95% CI 0.75 t 1.03; p< fr nn-inferirity and p= 0.12 fr superirity) Clinically relevant bleeding event rate was 14.9% with rivarxaban as against 14.5% per year in the warfarin grup, intracranial haemrrhage ccurred less frequently with rivarxaban (0.5% v/s 0.7% per year; p=0.02) as did fatal bleeding (0.2% v/s 0.5% per year p=0.003) Rivarxaban was thus shwn t be nn-inferir t warfarin in preventing strkes r systemic emblism in peple with atrial fibrillatin wh are at mderate t high risk fr a strke, while demnstrating a cmparable risk f majr and nn-majr clinically significant bleeding. Intracranial haemrrhage ccurred less frequently than with warfarin, but the incidence f gastrintestinal bleeding increased. The trial methdlgy increases the cmplexity in interpreting the efficacy data see Apixaban Apixaban is an ral direct factr Xa inhibitr administered as a fixed-dse that des nt require labratry mnitring and, unlike warfarin, has n knwn fd and few drug interactins. The ARISTOTLE was a duble blind, duble dummy randmized cntrlled trial which examined the effects f apixaban n the risk f strke r systemic emblism in patients with AF. It cmpared apixaban 5 mg twice a day with adjusted-dse warfarin (target INR 2.0 t 3.0) in 18,201 patients with AF and at least ne additinal risk factr fr - 6 -

7 strke (mean CHADS 2 scre 2.1), ver a median fllw-up f 1.8 years. The trial was designed t test fr nn-inferirity, but demnstrated the superirity f apixaban (a prespecified analysis). The rate f the primary utcme (ischaemic r haemrrhagic strke r systemic emblism) was 1.27% per year in the apixaban grup cmpared with 1.60% per year in the warfarin grup (HR with apixaban 0.79, 95% CI 0.66 t 0.95, p<0.001 fr nninferirity; p=0.01 fr superirity, NNT ver 1.8 years 168, 95%CI 95 t 773). The rate f majr bleeding was 2.13% per year in the apixaban grup and 3.09% per year in the warfarin grup (HR 0.69, 95%CI 0.60 t 0.80 p<0.001, NNT ver 1.8 years 66, 95%CI 48 t 110), and the rates f death frm any cause were 3.52% and 3.94%, respectively (HR 0.89, 95%CI 0.80 t 0.998, p=0.047, NNT ver 1.8 years 132, 95%CI 67 t 6951). The risk f the cmpsite utcme f strke, systemic emblism, MI r death frm any cause was reduced in the apixaban grup: HR 0.88 (95%CI 0.80 t 0.97, p=0.01, NNT ver 1.8 years 91, 95%CI 51 t 406). The risk f the net clinical utcme f strke, systemic emblism, majr bleeding r death frm any cause was als reduced in the apixaban grup: HR 0.85 (95%CI 0.78 t 0.92, p<0.001, NNT ver 1.8 years 56, 95%CI 36 t 117). Statistical analysis is nt presented, but the adverse event rates appear similar in bth study grups, including the rates fr disturbances f liver functin tests. Fewer patients in the apixaban grup discntinued the study drug befre the end f the study: 25.3% (3.6% due t death) versus 27.5% (3.8% due t death) in the warfarin grup, p= Study Cmparisns Differences amng study ppulatins, study designs, and times within target INR range (fr patients randmised t warfarin) limit the cmparisns which can be drawn between apixaban, dabigatran and rivarxaban. Fr example, patients in ROCKET AF (rivarxaban) had a higher risk f strke at baseline than thse in ther studies. As an editrial accmpanying ARISTOTLE pints ut, in all the studies the reductins in the primary efficacy end pint which included haemrrhagic as well as ischaemic strke were greatly influenced by a marked reductin in the risk f haemrrhagic strke. Of the three drugs, nly dabigatran at a dse f 150 mg als significantly reduced the risk f ischaemic strke cmpared with warfarin. Pint estimates fr reductin in risk f strke and reductin in all-cause mrtality were similar in all studies. Hwever, nly apixaban has s far been shwn t exhibit the cmbinatin f being significantly superir t warfarin in terms f strke reductin; all-cause mrtality; and fatal, majr, and nn-majr bleeding; with n statistically significant increase in risk f MI. The NICE Cmmittee cncluded that the netwrk meta-analysis results, submitted by the manufacturer f apixaban, shuld be interpreted with cautin (fr example, because f the differences in baseline characteristics between the study ppulatins) and were nt sufficiently rbust t reliably differentiate between apixaban, rivarxaban and dabigatran. The Cmmittee als cncluded that there was insufficient evidence t - 7 -

8 distinguish between the cst effectiveness f apixaban, dabigatran and rivarxaban at this time. Prbably the biggest gap in the evidence relating t all these drugs, including apixaban, is the limited lng term safety and efficacy data. The lng term effects f dabigatran are being evaluated in an nging fllw-up study (RELY-ABLE) f patients enrlled in RE- LY. Lng term effects f apixaban are similarly being investigated in the Lng Term Open label extensin f AVERROES (a trial versus aspirin). 3. Guidance aims and chice f NOAC This guidance has been prduced t help identify thse patients wh are mst likely t benefit frm a NOAC in this clinical situatin and t prvide advice n using the NOACs in the safest pssible manner. The guideline cvers bth newly identified patients and existing patients currently taking warfarin. The guidance des nt and shuld nt ver-ride the NICE TAs. A clinician may initiate dabigatran, rivarxaban r apixaban fr any patient within the Technlgy Appraisals criteria (as per sectin 1 abve). The guidance is based n the NICE TAs but includes the advice and pinins f lcal clinicians. Additinal guidance t that prvided by the NICE TA is ffered in rder t take int accunt sme f the fllwing issues - In RE-LY, the INR was within the therapeutic range fr 64% f the time. Althugh, this seems lw, this is similar t ther cntemprary trials f warfarin and, in this trial, may reflect the high prprtin f peple in the study wh had nt received warfarin previusly. Nevertheless, sme patients will have been mre cntrlled than thers, and the study des nt address the issue f whether dabigatran wuld be as effective as warfarin in thse peple wh were well cntrlled n warfarin. In ROCKET AF, amng patients in the warfarin grup, INR values were within the therapeutic range (2.0 t 3.0) a mean f 55% f the time (median, 58%; interquartile range, 43 t 71). The effect f rivarxaban did nt differ acrss the level f centre TTR. In ARISTOTLE, the INR was within the therapeutic range fr a mean f 62.2% f the time. The average TTR at Kettering General hspital is 68% and at NGH it is 71%. The average age f the patients in the RE-LY, ROCKET AF and ARISTOTLE was 71, 73 and 69 respectively; the average age f patients taking warfarin in the Nrth Nrthamptnshire ppulatin is 77 and Suth Nrthamptnshire fr females is 73 and males is 71. Sme f these patients may therefre have different risk/ benefit prfiles relating t these drugs than the trial patients. Mre patients discntinued treatment with dabigatran than warfarin during the RE-LY study, which might be due t prer tlerability. A higher incidence f discntinuatins that were a result f serius side effects supprts this view. Annual - 8 -

9 discntinuatin rates in ROCKET AF were similar between warfarin and rivarxaban (22.2% vs 23.7%). Althugh, majr bleeding was n mre frequent between grups verall, the higher risk f GI side effects (bth dses) and GI bleeding with dabigatran at the 150mg dse cmpared with warfarin raises questins abut its use in peple wh are at high risk f these effects. This was despite the fact that RE-LY excluded patients with a previus GI bleed. Majr bleeding frm a gastrintestinal site was als mre cmmn in the rivarxaban grup than the warfarin grup in ROCKET AF. One f the advantages f the NOACs is that they d nt require rutine mnitring; hwever ne f the drawbacks is the lack f readily available tests t quantify the degree f under r ver cagulatin. Specific tests are becming available. A nrmal thrmbin time and a nrmal APTT wuld indicate that a high level f dabigatran is unlikely in the patient. A calibrated diluted thrmbin time may prvide further infrmatin regarding the degree f anticagulatin with dabigatran and a specific anti-xa assay calibrated fr rivarxaban r apixaban can help determine the degree f anticagulatin assciated with the ral factr X inhibitrs. Given that rivarxaban and apixaban have a high degree f albumin binding in plasma they are nt dialysable. Whereas the clearance f dabigatran can be enhanced by dialysis if it available. Dabigatran is nt suitable fr patients with CrCl < 30 ml/min and requires regular tests f renal functin. Rivarxaban and apixaban shuld be used with cautin in patients with CrCl ml/min and are nt suitable fr patients with a CrCl <15 ml/min The best methd fr reversing the NOACs is nt knwn. Studies in human vlunteers have shwn that Prthrmbin Cmplex Cncentrate (PCC) can reverse the labratry abnrmalities caused by rivrxaban, but nt dabigatran. Hwever bth drugs are assciated with a nnlinear relatinship between the prlngatin f cagulatin tests and bleeding tendency and drug levels, and it remains uncertain whether PCC is a clinically effective methd f reversing these drugs. All the measurable (labratry) anticagulant effects f rivarxaban are reversed by PCC (Beriplex/Octaplex). Clinical data is lacking but it seems reasnable t give a dse f 25 IU/kg f PCC in cases f acute uncntrllable bleeding. PCC wrks in this setting because it prvides additinal factr II, VII, IX and X and the Xa inhibitr (rivarxaban) is vercme. The prduct literature fr apixaban suggests cnsidering recmbinant factr VIIa (rviia) in the setting f uncntrlled life threatening bleeding assciated with apixaban. Clinical evidence fr reversal f apixaban is lacking but, given the cmmn mde f actin, it wuld be expected that reversal wuld be alng the lines f that advised fr rivarxaban. PCC (Beriplex/Octaplex) and rviia have nt been fund t be effective in dabigatran reversal. This may be explained by the fact that dabigatran inhibits the last enzymatic step f the cagulatin cascade. Any agent that replaces cagulatin - 9 -

10 factrs prximal t thrmbin will nt cmpensate fr the prfund terminal defect in haemstasis. Activated PCC (FEIBA) may imprve haemstasis by prviding small amunts f thrmbin, hwever clinical data t date is lacking. In the absence f an effective antidte and until new data are available it wuld seem reasnable t ffer PCC, rviia r activated PCC t patients with life threatening bleeding assciated with dabigatran after evaluatin f the risk versus benefit.in an individual case. Lng term safety and tlerability f these new agents is nt yet knwn. All 3 are black triangle drugs. Nn-cmpliant patients were excluded frm RE-LY, and they might receive less (if any) benefit frm dabigatran, because the lng half-life f warfarin culd prvide them with a mre cnsistent anticagulant effect. Warfarin cannt usually be put int a Mnitred Dsage System due t the need fr dse adjustments. Dabigatran is unstable after being remved frm the blister pack and is therefre als nt suitable fr administratin using MDS bxes. Rivarxaban and apixaban may be put int an MDS. The effects f nn-cmpliance with the NOACs might be mre significant because f their shrt half-lives cmpared t warfarin

11 In summary the fllwing factrs need t be cnsidered in selecting a NOAC fr SPAF Dabigatran Rivarxaban Apixaban (Nte that the trials cmpared different levels f INR rates TTR was 64% in RE-LY, 62% in ARISTOTLE and 55% in ROCKET AF) Efficacy in strke preventin cmpared t warfarin Overall n difference Superir (150mg bd dse) Overall n difference Nn inferir (ITT analysis) Overall superir Superir fr haemrrhagic strke Nn-inferir (110mg bd dse) N difference fr ischaemic and uncertain type strke Reduced risk f bleeding cmpared t warfarin Evidence fr reduced bleeding risk at lwer dse. Equivalent t warfarin (except reduced ICH) Superir NB Increased risk f GI bleed than warfarin at higher dse which is the usual dse. Overall reduced intra cranial haemrrhage (ICH) Reversibility Uncertain. Uncertain Uncertain If last dse taken in last 2 hurs cnsider ral activated charcal. PCC, rvii r activated PCC can be cnsidered after risk v benefit assessment Area Under Curve may be reduced using activated charcal PCC, rvii r activated PCC can be cnsidered after risk v benefit assessment PCC, rvii r activated PCC can be cnsidered after risk v benefit assessment Dialysable Yes, but will need t be carried ut fr at least 6 hurs in rder t ensure adequate drug clearance N N Dsing bd d bd Drug interactins P- glycprtein substrates Simultaneus PGP & CYP-3A4 Simultaneus PGP & CYP-3A4 Drug cautins (increased bleeding risk) Other anticagulants (except during switching) Antiplatelet agents, NSAIDs, SSRIs r SNRIs Other anticagulants (except during switching), Antiplatelet agents, NSAIDs Other anticagulants (except during switching), Antiplatelet agents, NSAIDs

12 Use in patients with swallwing difficulties Cannt be crushed May be crushed and put thrugh NG tube but this is utside f license May be crushed and put thrugh NG tube but this is utside f license Suitability fr MDS Nt suitable Suitable Suitable Cst / year (Csts fr dabigatran and rivarxaban may vary in different settings because f negtiated prcurement discunts) 803* 767* 803 Pssibility f using in ther cnditins NICE apprved fr rthpaedic prphylaxis. Phase III data shws efficacy in DVT but n NICE appraisal currently planned NICE apprved fr rthpaedic prphylaxis. NICE apprved fr the treatment f DVT, and the preventin f recurrent DVT and PE fllwing an acute DVT in adults. NICE apprved fr rthpaedic prphylaxis

13 4. Selectin f apprpriate patients 4.1 Newly diagnsed AF patients This shuld be used in cnjunctin with the East Midlands Cardivascular Netwrk guideline fr selectin f patients with a CHADS 2 r CHA 2 DS 2 -VASc 1 requiring ral anticagulant strke thrmbprphylaxis. This can be fund at AF Pathway r at appendix 4. Warfarin remains a suitable first-line ral anticagulant fr mst patients Warfarin shuld be the preferred ptin in patients: with egfr < 30 mls/min (NB Patients with a baseline egfr f mls/min are at risk r prgressive/acute renal dysfunctin and the ptential risks f bleeding with NOACs shuld be weighed n an individual basis) with a histry f significant peptic ulcer disease significant ischaemic heart disease in absence f ther determining cnsideratins NOACs may be the preferred ptin in patients: predicted t have variable interacting medicatins e.g. recurrent antibitics with knwn excess use f ethanl wh wuld require dmiciliary testing with high HASBLED scre where dabigatran 110mg bd dsing shuld be cnsidered In all ther patients, warfarin is recmmended as a first line treatment fllwing discussin with patient explaining: lack f lng term data n NOACs issues cncerning reversibility NICE guidance and evidence base n dabigatran / rivarxaban / apixaban principles used in patient selectin patient will be cnsidered fr a NOAC if TTR < 60% after 4 mnths in presence f cmpliance 4.2 Existing patients currently taking vitamin K antagnists This shuld be used in cnjunctin with the East Midlands Cardivascular Netwrk guideline fr selectin f patients with a CHADS 2 r CHA 2 DS 2 -VASc 1 requiring ral anticagulant strke thrmbprphylaxis. Warfarin remains a suitable first-line ral anticagulant fr mst patients Cnversin t NOACs will be recmmended fr patients: intlerant f vitamin K antagnists TTR < 60% after > 4 mnths (prviding n evidence nn-cmpliance)

14 4.2.2 Cnversin t NOAC may be cnsidered fr patients: with histry f significant bleed n warfarin (dabigatran 110mg bd r apixaban preferred) with histry f strke r TIA while taking warfarin (prviding n evidence nncmpliance) requiring dmiciliary phlebtmy Other patients wh are well cntrlled and tlerant f warfarin are nt recmmended t change. 5. Pathway fr initiatin 5.1 Newly diagnsed AF patients GP r referring clinician t check FBC, U&E, LFT and a cltting screen CHADS 2 / CHA 2 DS 2 VaSc refer t anticagulant department fr cunselling, inductin and selectin f preferred anticagulant agent If NOAC preferred agent (selectin criteria abve), the anticagulant department will: deliver inductin cunselling supply initial 4 week supply f NOAC enter n acute trust database refer back t Primary Care fr further prescriptins and mnitring Cntent f Inductin Cunselling effect f drug risks (and benefits) f drug risk /benefit f NOAC versus warfarin advice regarding platelet antagnists imprtance f cmpliance ntificatin f health prfessinals / use f alert card management f prcedures infrmatin leaflet including list f knwn drug interactins patients shuld seek urgent medical attentin if they fall r injure themselves during treatment, especially if they hit their head, due t the increased risk f bleeding

15 5.1.3 When patient is referred frm cardilgy department with planned cardiversin New NOAC will be started in cardilgy. Currently there is insufficient data n either rivarxaban r apixaban in the setting f cardiversin s dabigatran is strngly preferred. A/C service will see within 5 wrking days t perfrm cunselling, registratin etc. (as abve) Patients shuld be reviewed in Cardilgy OP department 4-6 weeks pst cardiversin t cnsider lnger term chice f OAC 5.2 Patients currently taking vitamin K antagnists Anticagulant department t screen database f existing patients fr all patients: with TTR < 60% histry f majr bleeding n warfarin with CHADS 2 r CHA 2 DS 2 VaSc 1 histry f strke / TIA n warfarin in dmiciliary testing service These patients will be seen in nurse led A/C assessment clinic: t establish cmpliance check U&E t explain ratinale fr cnversin t manage cnversin 1. stp warfarin 2. supply 4 weeks NOAC 3. start NOAC after discntinuatin f warfarin as per guidance in prduct literature, (instructins t be written in Warfarin bk) letter t be sent t GP explaining utcme f abve and recmmendatins cncerning mnitring The fllwing patients will be referred frm the nurse led clinic t haematlgy cnsultant led clinic: patients with h/ significant bleeding r high HASBLED scre uncertainty abut cmpliance 6. Shared Care Guidance 6.1 Infrmatin letter t be supplied t GP 6.2 Recmmended mnitring twice yearly U&E if renal functin nrmal 3 mnthly U&E if renal functin abnrmal annual clinical review t assess risk / benefit 1. h/ strke / TIA 2. check HASBLED including any bleeding episdes with a view t dse reductin r referral back t specialist clinic

16 Appendix 1 Letter t Primary Care fllwing initiatin f Dabigatran fr Strke Preventin in AF Dear Dr Yur patient has tday been started n dabigatran t prevent strke assciated with atrial fibrillatin. The decisin t d s has been made n the basis f: predicted high risk n warfarin (plypharmacy, excess ethanl, high bleeding risk scre) previus pr cntrl n warfarin Time in Treatment Range <60% Histry f significant bleeding n warfarin Histry f strke r TIA n warfarin CHADS 2 r CHA 2 DS 2 VASc HASBLED and egfr Yur patient has been prescribed: Dabigatran 150mg bd OR Dabigatran 110mg bd (preferred because f identified high risk f bleeding) Yur patient has been cunselled abut the safe use f dabigatran supplied with the attached infrmatin leaflet supplied with an alert card The fllwing mnitring is recmmended fr patients n dabigatran U&E and FBC Nrmal renal functin 6 mnthly Abnrmal r unstable renal functin 3 mnthly Annual review Histry f any strke / TIA r bleeding in last year recheck HASBLED if HASBLED nw high, r bleeding events, cnsider either reductin t 110 mg bd, r specialist assessment

17 It des nt require INR mnitring DABIGATRAN KEY POINTS It must be stpped if egfr <30 mls/min At standard dse (150mg bd) it has the same risk f majr bleeding (but nt intracranial haemrrhage) as warfarin. Dabigatran T½ is hurs nly, in presence f nrmal renal functin. Cmpliance is critical therefre, as prtectin frm strke will be lst with missin f nly ne dse (in cntrast t warfarin). In the event f surgery r prcedures, it will be necessary t mit the dse prir t the prcedure. See prduct SPCs fr full details f timescales. Dabigatran must nt be used in patients with a lesin r cnditin putting them at significant risk f majr bleeding (see SPC fr details). Cncmitant treatment with ther anticagulants is cntraindicated while n dabigatran Its use is cntraindicated with: Ketcnazle, itracnazle, vricnazle, psacnazle Ciclsprin Tacrlimus Drnedarne Prtease inhibitrs Rifampicin, carbamazepine, phenytin and St. Jhns wrt It shuld be used with cautin with ther p glycprtein substrates e.g verapamil (in which case the dse f dabigatran shuld be reduced t 110mg bd) and amidarne, quinidine and clarithrmycin especially if mild r mderate renal impairment. It causes prlngatin f APTT and TT which are nt hwever measures f the degree f anticagulatin. A nrmal TT will rule ut the presence f any significant anticagulant effect frm dabigatran There is n established methd acutely t reverse the effect f dabigatran. In the event f suspected verdse, activated charcal shuld be administered within 2 hurs f ingestin. As f February 2013 dabigatran is nw cntraindicated in patients with prsthetic heart valves requiring anticagulant treatment. The existing warning in sectin 4.4 f the SPC nt t use the drug in patients with prsthetic heart valves is strengthened t a cntraindicatin based n the availability f new data frm clinical trials. Fr further infrmatin r advice, please cntact the KGH Anticagulant service n bleep 541 r the NGH Anticagulant service n

18 Appendix 2 Letter t Primary Care fllwing initiatin f Rivarxaban fr Strke preventin in AF Dear Dr Yur patient has tday been started n rivarxaban t prevent strke assciated with atrial fibrillatin The decisin t d s has been made n the basis f: Predicted high risk n warfarin (plypharmacy, excess ethanl, high bleeding scre) Previus pr cntrl n warfarin Time in treatment range <60% Histry f significant bleeding n warfarin Histry f strke r TIA n warfarin CHADS 2 r CHA 2 DS 2 VASc HASBLED and egfr Yur patient has been prescribed: Rivarxaban 20mg d OR Yur patient: Rivarxaban 15 mg d Has been cunselled abut the safe use f rivarxaban Supplied with the attached infrmatin leaflet Supplied with an alert card The fllwing mnitring is recmmended* fr patients n rivarxaban Base line FBC, renal functin, LFTs and cltting Renal functin and LFTs mnthly fr first 3 mnths then 3 mnthly Annual review Histry f any strke/ TIA r bleeding in the last year Recheck HASBLED and egfr If HASBLED nw high, r bleeding events r egfr between ml/min, dse f Rivarxaban shuld be reduced t 15mg d r refer fr specialist assessment *lcal recmmendatin; nt in SPC

19 It des nt require INR mnitring RIVAROXABAN KEY POINTS If egfr <15 mls/min rivarxaban must nt be initiated and if already initiated, must be stpped In patients with hepatic disease assciated with cagulpathy and clinically significant bleeding risk, including cirrhtic patients rivarxaban shuld nt be prescribed Rivarxaban must nt be used in patients with a lesin r cnditin putting them at significant risk f majr bleeding (see SPC fr details). Cncmitant treatment with ther anticagulants is cntraindicated while n rivarxaban Rivarxaban has a t½ f 5-9 hurs in yung patients and hurs in elderly patients s cmpliance is crucial In the event f surgery r prcedures, rivarxaban shuld be stpped 24 hurs prir t the interventin. It interacts with the fllwing drugs: Cntraindicated Azle antifungals: ketcnazle, vricnazle, itracnazle, psacnazle HIV prtease inhibitrs i.e. ritnavir Drnedarne Use with cautin Rifampicin, Phenytin, carbamazepine, phenbarbitl, St.Jhn s wrt Rivarxaban causes an increase principally in PT, but this is nt a measure f degree f anticagulatin There is n established methd acutely t reverse the effect f rivarxaban. Fr further infrmatin r advice please cntact the KGH Anticagulant service n bleep 541 r the NGH Anticagulant service n

20 Appendix 3 Letter t Primary Care fllwing initiatin f Apixaban fr Strke preventin in AF Dear Dr Yur patient has tday been started n apixaban t prevent strke assciated with atrial fibrillatin The decisin t d s has been made n the basis f: Predicted high risk n warfarin (plypharmacy, excess ethanl, high bleeding scre) Previus pr cntrl n warfarin Time in treatment range <60% Histry f significant bleeding n warfarin Histry f strke r TIA n warfarin CHADS 2 r CHA 2 DS 2 VASc HASBLED and egfr Yur patient has been prescribed: OR Apixaban 5mg bd Apixaban 2.5 mg bd (if CrCl mls/min and in patients with either at least tw f the fllwing: (age 80 years, bdy weight 60 kg, r serum creatinine 133 micrmle/l) Yur patient: Has been cunselled abut the safe use f apixaban Supplied with the attached infrmatin leaflet Supplied with an alert card The fllwing mnitring is recmmended fr patients n apixaban Base line FBC, renal functin, LFTs and cltting Renal functin and LFTs mnthly fr first 3 mnths then 3 mnthly Annual review Histry f any strke/ TIA r bleeding in the last year Recheck HASBLED and egfr If HASBLED nw high, r bleeding events r egfr between 15-30ml/min, reduce dse t 2.5mg bd r refer fr specialist assessment