Awaiting DC-cardioversion or urgent AF ablation within 4 weeks [dabigatran only]

Transcription

1 RIVAROXABAN fr the preventin f strke and systemic emblism in nn-valvular atrial fibrillatin: supprting practical guidance fr primary care (NCL Jint Frmulary Cmmittee website NOAC Intrductin: indicatin and licensing NICE TA recmmended rivarxaban (Xarelt ) as an ptin fr the preventin f strke and systemic emblism within its licensed indicatin i.e. in adult patients with nn-valvular atrial fibrillatin with ne r mre risk factrs such as: cngestive heart failure hypertensin age 75 years diabetes mellitus prir strke r transient ischaemic attack Rivarxaban is an rally active direct Anti-Xa inhibitr. ROCKET-AF 2 was a large, prspective, randmised cntrlled trial in ver 14,000 patients with CHADS 2 scre > 2 that cmpared rivarxaban t adjusted dse warfarin (INR range 2.0 t 3.0). Patients with CrCL < 30mL/min as estimated by Cckcrft & Gault were excluded frm the trial. The primary efficacy utcme was the cmpsite f strke (ischemic r hemrrhagic) and systemic emblism whilst the principal safety end pint was a cmpsite f majr and nn-majr clinically relevant bleeding events. ROCKET-AF demnstrated nn inferirity with in the primary endpint (cmpsite f ischaemic r haemrrhagic strke and systemic embli) with incidences f 1.7% per-100 patient years in the rivarxaban arm versus 2.2% in the warfarin arm; p < Majr and nn-majr clinically relevant bleeding was nt significantly different between the tw grups. Intracranial haemrrhage ccurred less ften with rivarxaban (0.5% versus 0.7%, HR 0.67; 95% CI 0.47 t 0.93; P = 0.02), as did fatal bleeding (0.2% per year vs. 0.5% per year, P = 0.003). Majr GI bleeding was mre cmmn with rivarxaban (3.2%) than with warfarin (2.2%, P<0.001), as were bleeds requiring transfusin (1.6% per year fr rivarxaban vs 1.3% per year fr warfarin; p=0.04). 2.0 Use acrss Nrth Central Lndn (NCL) The new ral anticagulants (NOAC) such as rivarxaban, dabigatran and apixaban, are all NICE apprved and are cnsidered alternatives t warfarin (currently standard treatment) fr the preventin f strke and systemic emblism in patients diagnsed with nn-valvular AF, with CHA 2 DS 2 VASc > 1 (excluding female gender) and assuming that NCL criteria are fulfilled (summarised in table belw). Rivarxaban is the preferred agent as per the NCL Jint Frmulary Cmmittee, althugh dabigatran r apixaban can be used where clinically justified NCL criteria Cmments Knwn allergy / intlerance t warfarin r ther vitamin K antagnist Significant technical difficulties with INR mnitring and/r accessing A/C clinic that raises safety cncerns Patient-time in range < 65% nce established n warfarin (nt due t wilful nn-cmpliance). INR 8.0 n 1 ccasin r INR > 5.0 n 2 ccasins ver a perid f 6 mnths (nce A/C is established), with a high likelihd f recurrence (i.e. unsafe) Phenindine supply issues Awaiting DC-cardiversin r urgent AF ablatin within 4 weeks [dabigatran nly] Specific clinical indicatin as per lcally designated cnsultant in strke medicine / thrmbsis / cardilgy e.g. alpecia with n ther cause (such as irn deficiency anaemia, hypthyridism etc) Cnsider alternatives such as cmmunity A/C services, dmiciliary mnitring/input r self-testing Nn-cmpliance is nt a reasn t switch t NOAC. Cnsider alternatives such as cmmunity A/C services, dmiciliary mnitring/input r self-testing Dabigatran is the nly NOAC currently licensed fr DC-cardiversin. All NOAC are unlicensed fr AF ablatin. If nging anticagulatin required pst prcedure (regardless f rhythm), then switch t warfarin unless any f the ther criteria listed in this table are fulfilled. Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

2 3.0 Patient pathway an verview (See appendix 1 fr cmplete AF NOAC pathway) Gvernance structures are required t ensure the safe and rbust intrductin f NOAC int rutine clinical practice. The use f secndary care anticagulatin clinics wuld fulfil this requirement and is the mdel agreed by NCL fr initiatin f NOAC. Decisin t anticagulate and NOAC criteria fulfilled GP*refers pt t lcal AC clinic using NOAC referral prfrma Hspital AC clinic initiates, prescribes and mnitrs NOAC fr 2 mnths** After 2 mnths, GP takes ver prescribing & mnitring GP t re-refer t lcal A/C clinic if needed *If urgent, then secndary care can directly refer patients t his/her lcal AC clinic fr utpatient initiatin ** Referral pathways may be subject t lcal variatin, but the minimum requirements are utlined abve 4.0 Rles and Respnsibilities 4.1 Referring clinician t: Calculate CHA 2 DS 2 VASc scre (see appendix 2) Risk assess patient fr anticagulatin (including the HAS-BLED scre see appendix 2) Check rutine bichemistry (FBC, U&E, LFT), calculate CrCL (using Cckcrft & Gault equatin, appendix 3), check cagulatin screen and bld pressure Cnfirm that NOAC is apprpriate, in line with NCL guidance Discuss risks vs. benefits f anticagulatin with the patient Cmplete the NOAC referral prfrma and refer patient t his/her lcal anticagulatin clinic fr NOAC cunselling and initiatin Fr patients identified in secndary care requiring anticagulatin fr AF: Outpatients: GP t refer t lcal anticagulatin clinic Outpatient strke neurlgists/physicians, r designated cardilgists/haematlgists may refer patient t his/her lcal A/C clinic directly in cases where urgent anticagulatin is required (as is dne currently); these patients may be n a lw mlecular weight heparin as an interim measure Inpatients: If urgent, IP team t refer t patient s lcal anticagulatin clinic fr OP initiatin. Otherwise, patient t be referred t the lcal anticagulatin clinic by GP In general, NOACs shuld nly be initiated by secndary care anticagulatin clinics, t ensure that rbust gvernance prcesses will be fllwed 4.2 Anticagulatin (A/C) clinic t: Check baseline blds as per nrmal practice: FBC, U&E, LFTs, cagulatin screen (if nt n A/C) r INR (if n warfarin) Select apprpriate NOAC after review f clinical data prvided n referral prfrma (rivarxaban is the preferred agent as per the NCL Jint Frmulary Cmmittee, althugh dabigatran r apixaban can be used where clinically justified) Scan referral prfrma int electrnic recrds (r file in medical ntes if frmer nt pssible) Deliver standardised verbal cunselling as per NCL/lcal checklist (patient t sign) Prvide (1) written infrmatin abut the drug and (2) a patient alert card (available frm the drug cmpany) Arrange an initial supply f 4 weeks (mnth 1) and prvide a fllw-up A/C clinic appintment within 4 weeks Infrm GP (standard NCL letter) that patient has been initiated n NOAC Review the patient within 4 weeks t assess tlerability and cmpliance. Assuming n cncerns, arrange the secnd mnth's prescriptin (NB: if there are cncerns, clinic t liaise with referring clinician / lcal haematlgist) After the secnd visit (when mnth 2 s prescriptin is issued) and assuming that patient will remain n NOAC, immediately infrm GP via standard transfer f care letter (fax and phne t cnfirm receipt f infrmatin) t ensure cntinuity f care and NOAC supply GP shuld aim t take ver care as frm the start f mnth 3. A/C clinic t ensure that GP agreement has been received (and scanned nt electrnic recrds r the equivalent) befre discharging patient frm the clinic Ensure patient understands the transfer prcess and hw t btain further supplies Enter details n lcal A/C database Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

3 4.3 GP respnsibilities As per pints listed under 4.1 if referring the patient Als: Update GP practice recrds, detailing that NOAC has been initiated (with mnths 1 and 2 being supplied by secndary care) During mnth 2 f treatment, sign the transfer f care frm t cnfirm agreement fr nging prescribing and mnitring as frm the start f mnth 3, and fax back t the anticagulatin clinic Reiterate the imprtance f patient cmpliance and review n a regular basis t avid accidental stppage. Reiterate the need t carry the patient alert card at all times Undertake apprpriate clinical mnitring (sectin 11.0) and be aware f pssible drug interactins Ntify ther healthcare prfessinals if patient is t underg any invasive treatments (e.g. dental r elective surgery) Undertake an annual review regarding the nging apprpriateness f anticagulatin, including a review f the cautins and cntraindicatins t rivarxaban Refer back t the lcal anticagulatin clinic if there are any clinical cncerns 5.0 Cntraindicatins and exclusin criteria t rivarxaban In Octber 2013, the MHRA strengthened the cntraindicatins fr all NOACs (dabigatran, rivarxaban and apixaban) 3a. Patients listed in the categries belw, shuld nt receive rivarxaban. Cntraindicatins / exclusins t use (nt exhaustive refer t Xarelt SPC 3 ) Lesin r cnditin, if cnsidered t be a significant risk factr fr majr bleeding. This may include: Current/recent upper r lwer GI ulceratin; esphageal varices (knwn r suspected); malignant neplasms at high risk f bleeding Surgery/trauma r bleed affecting head/brain, eyes r spine within last 4 weeks AV malfrmatins, vascular aneurysms r majr intraspinal / intracerebral vascular abnrmalities Strke in last 14 days/severe strke in last 6 mnths (unless advised by designated strke neurlgy cns) Uncntrlled hypertensin (systlic BP > 180mmHg and/r diastlic BP > 100mmHg), vascular retinpathy Hepatic disease assciated with cagulpathy and clinically relevant bleeding risk including cirrhtic patients with Child Pugh B and C CrCL < 15mL/min (calculated as per C&G frmula) Pregnancy and lactatin (crsses placenta and int breast milk) Indicatins nt cvered by licence e.g. prsthetic heart valve(s) requiring anticagulatin; INR range higher than required Cntraindicated: cncmitant treatment with ther anticagulants, except when switching t r frm rivarxaban (as advised by A/C clinic, haematlgy SpR r haemstasis cnsultant), r when unfractinated heparin is given at dses necessary t maintain an pen central venus r arterial catheter Nt recmmended: systemic ketcnazle, itracnazle, psacnazle, vricnazle, HIV prtease inhibitrs Avid: drnedarne 6.0 Cautins Patients falling int the fllwing categries shuld be discussed with the lcal haematlgist. Cautins t use (nt exhaustive refer t Xarelt SPC 3 ) Histry f previus majr bleed n anticagulatin / antiplatelet therapy Thrmbcytpenia (e.g. platelets < 75) Abnrmal baseline cagulatin screen (repeat and investigate befre initiatin f NOAC) Weight < 50 kg r > 120kg Abnrmal liver functin tests (2 x upper limit f nrmal) Myelprliferative disease / sickle sell disease (limited evidence n use) Cngenital r acquired bleeding disrders Antiplatelets, NSAIDs, rifampicin, phenytin, phenbarbitne, carbamazepine, St Jhn s Wrt refer t SPC 3 and table 2 Age > 75 years; discuss with lcal haematlgist if additinal risk factrs fr bleeding Excessive alchl intake High risk f recurrent falls resulting in significant injury Patients < 18 years (unlicensed discuss with haematlgist) Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

4 Nte: the cncmitant use f aspirin r ther antiplatelets with rivarxaban significantly increases the risk f majr bleeding. All antiplatelet (and NSAID) use must be reviewed prir t initiating rivarxaban. See sectins 7.0 and Dse and administratin The standard licensed dse f rivarxaban fr AF is 20mg OD (15mg OD in specific circumstances see belw) CAUTION: the 10mg rivarxaban tablet is licensed fr VTE thrmbprphylaxis in elective hip r knee replacement surgery. Please ensure that nly the 15mg/20mg strength tablets are prescribed r dispensed fr AF, t minimise drug errrs and patient cnfusin Nte that plasma levels and excretin f rivarxaban are affected by many variables including renal functin and drug interactins see belw fr further infrmatin and fr advice re dse adjustments Rivarxaban must be taken with fd t maximise biavailability Bth the 20mg and the 15mg tablets are film-cated, but are nt mdified r cntrlled release. Crushing the tablets fr patients wh are unable t swallw wuld nt be expected t affect the release characteristics per se, but wuld make it an unlicensed administratin methd (clinical decisin and respnsibility) If a dse is missed, then the patient shuld take rivarxaban as sn as it is remembered (- lcal practice at UCLH is t limit this t within 8 hurs). Cntinue with the next dse the fllwing day as usual. The dse shuld nt be dubled within the same day t make up fr a missed dse The tablets can be dispensed int medicatin reminder devices if apprpriate Frmulatin cntains lactse: avid in patients with rare hereditary prblems f galactse intlerance, the Lapp lactase deficiency r glucse-galactse malabsrptin Table 1: Rivarxaban dsing fr specific patient grups Usual standard dse fr AF: Rivarxaban 20mg OD Plasma levels and excretin f rivarxaban can be affected by many variables including renal functin and drug interactins. If there are a number f risk factrs fr bleeding, then recnsider the verall risk vs benefit f treatment with rivarxaban Risk factrs fr bleeding with rivarxaban Rivarxaban dsing cmments (refer t SPC 3 ) HAS-BLED scre > 3 and where anticagulatin is Cnsider 15mg OD in line with recmmendatins frm The apprpriate Eurpean Sciety f Cardilgy (ESC) 4 Histry f gastritis, esphagitis r gastr-esphageal reflux disease and where anticagulatin is apprpriate Lw bdyweight (e.g. < 50kg) Renal impairment* CrCL 15-49mL/min Renal impairment* CrCL < 15mL/min Increased risk f majr GI bleeding cmpared t VKA If rivarxaban apprpriate, then PPI cver advised. Limited data available - discuss with lcal haematlgist Reduce dse t 15mg OD (SPC fr AF) (NB: limited clinical data with CrCL 15-29mL/min; plasma cncentratins significantly ) D NOT use rivarxaban (SPC) Antiplatelet agents Cncmitant use f antiplatelet agents increases the risk f majr bleeding - see table 2 fr further infrmatin NSAIDS Increased risk f bleeding - see table 2 SSRIs (Selective Sertnin Re-uptake Inhibitrs) / May increase risk f bleeding see table 2 SNRIs (Selective Nrepinephrine Re-uptake Inhibitrs) Certain drug interactins See table 2 *estimated CrCL using C&G frmula (appendix 3) Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

5 8.0 Drug interactins with rivarxaban 3 Rivarxaban is metablised via CYP3A4, CYP2J2 and CYP-independent mechanisms. It is als a substrate f the transprter prteins P-glycprtein (P-gp) and breast cancer resistance prtein (Bcrp) Active substances strngly inhibiting nly ne f the rivarxaban eliminatin pathways, either CYP3A4 r P-gp, are expected t increase rivarxaban plasma cncentratins t a lesser extent, than thse strngly inhibiting bth pathways Table 2: Drug interactins with rivarxaban 3 (NB: list is NOT exhaustive) Drugs (examples) Effect (SPC 3 ) with examples Actin (SPC 3 ) Systemic azle antimyctics, such as: ketcnazle itracnazle vricnazle psacnazle (These are strng inhibitrs f bth CYP3A4 and P-gp pathways) rivarxaban plasma cncentratins expected, leading t increased risk f bleeding Ketcnazle AUC (2.6 fld) and C max (1.7 fld) Cncmitant use is nt recmmended NB: flucnazle is a mderate CYP3A4 inhibitr and its interactin with rivarxaban is nt cnsidered t be clinically relevant HIV prtease inhibitrs e.g. ritnavir (Strng inhibitr f bth CYP3A4 and P-gp pathways) rivarxaban plasma cncentratins expected, leading t increased risk f bleeding Cncmitant use is nt recmmended Ritnavir AUC (2.5 fld) and C max (1.6 fld) Drnedarne Limited available clinical data Avid cncmitant use Ptent CYP3A4 and Pssible plasma cncentratin in patients Use with cautin mderate P-gp inhibitrs with renal impairment (frm pharmackinetic e.g. clarithrmycin / mdelling studies) telithrmycin) Strng CYP3A4 inducers Rifampicin Phenytin Carbamazepine Phenbarbitne St. Jhn's Wrt (Hypericum perfratum) Anticagulants such as unfractinated heparin, LMWH (dalteparin, enxaparin etc), fndaparinux, ther ral anticagulants (warfarin, dabigatran, apixaban etc) Thrmblytic agents, GPIIb/IIIa inhibitrs rivarxaban plasma cncentratins expected. Rifampicin mean AUC f rivarxaban by apprximately 50 %. Other strng CYP3A4 inducers (examples given), may als lead t rivarxaban plasma cncentratins. Increased risk f majr bleeding Increased risk f majr bleeding Use with cautin Cmbinatin cntraindicated, except when switching therapy t r frm rivarxaban (as advised by A/C clinic / haemstasis SpR r Cnsultant), r when unfractinated heparin is given at dses necessary t maintain a patent central venus r arterial catheter Interactin nt specifically mentined in the SPC, but advise avid cmbinatin d/w haemstasis cnsultant shuld the situatin arise Aspirin / clpidgrel Increased risk f majr bleeding Stp antiplatelet agents UNLESS anther specific clinical indicatin (ther than AF) exists. If cncmitant therapy unavidable (and a careful risk-benefit assessment has been made) then review the mst apprpriate drug cmbinatin. PPI cver advised. Clse clinical mnitring required Other antiplatelet agents (e.g. Ticldipine / prasugrel / ticagrelr) Likely increased risk f majr bleeding Interactin nt specifically mentined in SPC; cmbinatin nt recmmended NSAIDs Increased risk f bleeding Avid if at all pssible. Careful risk-benefit assessment required. If benefit f chrnic NSAID utweighs risk f bleeding, then PPI cver advised. Clse clinical mnitring required SSRIs (Selective sertnin reuptake inhibitrs) / SNRIs (selective nrepinephrine re-uptake inhibitrs) May increase risk f GI bleeding Interactin nt specifically mentined in the SPC - use with cautin. If ther risk factrs fr bleeding present, then cnsider GI cver; clse clinical mnitring required Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

6 9.0 Cnverting frm VKA r lw mlecular weight heparin (LMWH) t rivarxaban Secndary care anticagulatin clinics will switch patients t rivarxaban. GPs shuld nt d this please. Recmmendatins frm the SPC 3 are utlined belw fr infrmatin nly: Vitamin K Antagnist (VKA e.g. warfarin) t rivarxaban Stp warfarin Start rivarxaban when the INR is < 3.0 (NB: a different recmmendatin exists fr VTE patients refer t SPC 3 ) LMWH t rivarxaban i.e. patients n lngterm therapeutic dse LMWH being switched t rivarxaban. (Fr anticagulatin arund elective prcedures, refer t sectin 12.0) Stp LMWH Start rivarxaban 0 t 2 hurs befre the time f the next scheduled administratin f SC LMWH 10.0 Adverse effects As wuld be expected, rivarxaban increases the risk f bleeding during treatment and patients shuld be mnitred fr signs f bleeding/anaemia Patients shuld be advised t seek medical advice if persistent r frequent episdes f bleeding ccur; he/she shuld seek urgent medical attentin if severe bleeding is experienced. Nte that there is currently n pharmaclgical antidte t rivarxaban. In case f intlerance t rivarxaban, patients shuld be instructed t cnsult their dctr as sn as pssible s that treatment can be reviewed and alternative ptins cnsidered. Discussin with the lcal haematlgy cnsultant / lcal anticagulant clinic is advised Cmmn side effects ( 1/100 t < 1/10) as listed in the SPC 3 include: dyspepsia, diarrhea, nausea, vmiting, hyptensin, edema and dizziness (nt exhaustive - refer t the current BNF r SPC fr further infrmatin) Frm varius phase 3 studies (different indicatins), mucsal bleeding (e.g. epistaxis, gingival, gastrintestinal, geniturinary) and anaemia were seen mre frequently during lng term rivarxaban treatment cmpared with warfarin/vka 3. Specifically frm ROCKET-AF 2 : Rivarxaban 20mg OD (15mg OD fr CrCL 30-49mL/min), resulted in similar rates f majr bleeding cmpared t warfarin (3.6% vs 3.4%, p=0.58). The rate f critical rgan bleeding was less with rivarxaban (0.8% vs 1.2%, p= 0.007), as were bth the risk f intracranial haemrrhage (0.5% vs 0.7%, p = 0.02) and the risk f fatal bleeding (0.2% vs 0.5% p=0.003). Decreases in haemglbin levels f > 2 g/dl and majr bleeding requiring transfusins were mre cmmn amng rivarxaban patients, as was majr bleeding frm a gastrintestinal site (3.2% vs 2.2%, p <0.001). Epistaxis (10.1% vs 8.6%) and haematuria (4.2% vs 3.4%) ccurred mre frequently with rivarxaban than with warfarin (p< 0.05). (All stats quted as event rate n./100 patient-yr) IMPORTANT: Lng-term safety/tlerability is nt yet knwn. These black triangle drugs and are being intensively mnitred. All suspected adverse drug reactins shuld be reprted t the MHRA either using the BNF yellw card system r nline at Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

7 11.0 Recmmended mnitring fr rivarxaban fr primary care Mnitring parameter FBC, U&Es, LFTs, bld pressure and HAS-BLED scre Cmment Prir t referral t lcal A/C clinic. (NB: these will be reviewed by the anticagulatin team) Thereafter, as clinically indicated (minimum annually) but see belw fr renal functin. Review if LFTs > 2 x upper limit f nrmal, platelets <100, r uncntrlled hypertensin Renal functin: nce initiated, mnitr as suggested in adjacent clumn (NB: patients > 75 years may require mre frequent mnitring) Reassess when decline suspected (e.g. hypvlaemia, dehydratin, certain c-medicatins etc.) Onging clinical surveillance, including: 1) Checking t avid accidental NOAC stppage 2) Checking fr pssible interactins with new medicines 3) Reinfrcing the imprtance f carrying the rivarxaban patient alert card at all times Annual clinical review t: 1) Assess the cntinuing need fr antithrmbtic therapy 2) Asses the risk vs. benefit f anticagulatin i.e. Histry f strke / TIA Bleeding risk using the HAS-BLED scre, including any bleeding episdes. NB: Rutine anticagulatin mnitring is NOT required est. CrCL (C&G frmula) Suggested mnitring frequency CrCL > 80mL/min Annually CrCL 50-79mL/min 6-12 mnthly CrCL 30-49mL/min Clse mnitring at discretin f clinician (minimum 3 mnthly)* CrCL 15-29mL/min Clse mnitring at discretin f clinician (minimum 3 mnthly)* CrCL < 15mL/min D nt use *dse reductin required fr AF: refer t Xarelt SPC 3 Thrughut the treatment perid and in line with general anticagulatin practice Cnsider whether current dse remains ptimal r whether dse reductin / referral back t specialist is required. Standard cagulatin parameters (e.g. Activated partial thrmbplastin time (APTT) and prthrmbin time (PT), may be affected t varying degrees, but d nt prvide quantitative infrmatin n the intensity f anticagulatin effect Management arund elective invasive prcedures / surgical interventins Nte that clinical experience with rivarxaban and bridging arund surgical prcedures is limited The management f anticagulatin arund elective prcedures shuld be in accrdance with the apprpriate lcal secndary care management guidelines - liaise with the lcal haematlgist/anticagulatin clinic In general, steps t fllw include: Several weeks pre-p, infrm surgen / ther clinician undertaking prcedure that patient is taking rivarxaban fr AF. Additinal useful infrmatin frm primary care includes CHA 2 DS 2 VASc scre and patient s bleeding histry. Rivarxaban will need t be stpped at least 24 hurs prir t the interventin, depending n renal functin / prpsed interventin (secndary care t advise). The T 1/2 is 5-9 hurs in yung healthy individuals, increasing t 11-13hurs in the elderly 3. Pst prcedure and depending n risks f bleeding vs thrmbsis, secndary care may advise initial pst-p management with thrmbprphylactic dses f LMWH, escalating t therapeutic dse LWMH (r rivarxaban see belw) when surgens happy and as per lcal bridging guidelines. Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

8 Rivarxaban t restart when there are n cncerns re surgical haemstasis, patient is eating and drinking and reinitiatin f therapeutic anticagulatin is apprpriate (peak levels usually reached apprx 2-4hurs pst dse 3 with steady state reached within apprx 2-3 days with nrmal renal functin). Hw t switch frm LMWH t rivarxaban (nly in the cntext f management f anticagulatin arund elective prcedures). Fr the rutine switch frm lngterm LMWH t new rivarxaban, refer t sectin 9.0 Stp LMWH Start rivarxaban apprx. 12hrs after last dse f prphylactic LMWH, 12hrs after last dse f therapeutic LMWH if in divided BD dse (e.g. dalteparin 100 units/kg SC BD) r 24hrs after last therapeutic nce daily LMWH dse (e.g. dalteparin 200units/kg SC OD). Fr minr prcedures including dental prcedures under LA/GA and at LOW RISK f bleeding: restart therapeutic dse rivarxaban (preadmissin dse) 6hrs pst prcedure, then 24hrly thereafter. This assumes surgical haemstasis is secured, ral absrptin is assured and immediate therapeutic A/C is safe t resume. Peak levels reached 2-4 hrs pst dse. Nte: If there are cncerns re therapeutic anticagulatin, cnsider prphylactic dse LMWH and d/w lcal haematlgist. Fr urgent acute interventins: cntact lcal haematlgist fr advice Additinal NCL infrmatin t supprt this dcument NCL Jint Frmulary Cmmittee website NOAC - NCL psitin statement n the use f NOAC fr the preventin f strke and systemic emblism in patients diagnsed with nn-valvular atrial fibrillatin at increased risk f strke (AF) NCL Summary treatment pathway fr Anticagulatin and AF NOAC referral prfrma GP NOAC ntificatin and transfer f care frms Guidelines fr bleeding (rivarxaban) - trusts t write lcal guidelines 14.0 Appendices Appendix 1: Summary treatment pathway: anticagulatin fr the preventin f strke and systemic emblism in nn-valvular AF Appendix 2: Risk assessment: CHA 2 DS 2 -VASc and HAS-BLED scring systems (AF patients) Appendix 3: Cckcrft & Gault (C&G)frmula (t estimate CrCL) Appendix 4: Rivarxaban cunselling checklist 15.0 References 1. NICE technlgy appraisal guidance 256. Rivarxaban fr the preventin f strke and systemic emblism in peple with atrial fibrillatin. May Patel MR et al. and the ROCKET AF Steering Cmmittee fr the ROCKET AF Investigatrs. Rivarxaban versus warfarin in nnvalvular atrial fibrillatin (and supplementary appendix). N Engl J Med 2011; 365: (a) MHRA Drug Safety Update 2013; Vl 7 (3). New ral anticagulants, apixaban (Elquis ), dabigatran (Pradaxa ) and rivarxaban (Xarelt ): risk f serius haemrrhage clarified cntraindicatins apply t all three medicines 3. Summary f prduct Characteristics. Xarelt 20mg & 15mg film cated tablets. Bayer Pharma AG. Date f first authrisatin/renewal f authrisatin: 30/09/08. Date f revisin June Available frm: 4. Camm AJ et al fcussed update f the ESC guidelines fr the management f atrial fibrillatin. Eur. Heart J : Lip et al. Refining clinical risk stratificatin fr predicting strke and thrmbemblism in Atrial Fibrillatin using a nvel risk factr-based apprach. The Eur Heart Survey n Atrial Fibrillatin. Chest 2010; 137(2): Pisters R et al. A nvel user-friendly scre (HAS-BLED) t assess 1 year risk f majr bleeding in patients with AF: The Eur heart survey. Chest 2010; 138: Cckcrft DW and Gault H. Predictin f creatinine clearance frm serum creatinine. Nephrn 1976;16: Basic Clinical Pharmackinetics 4th editin; Michael Winter. Editr: DB Try. Lippinctt Williams& Wilkins, Philadelphia Dcument written n behalf f NCL by: Ms Carlyn Gates, Lead pharmacist, Thrmbsis & Anticagulatin, UCLH NHS Fundatin Trust Dr Hannah Chen, Cnsultant haematlgist, UCLH NHS Fundatin Trust Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

9 Appendix 1: Summary treatment pathway: Anticagulatin fr the preventin f strke and systemic emblism in nn-valvular atrial fibrillatin (AF) ALL referrers (primary & secndary care) Risk assess fr strke preventin (CHA 2 DS 2 VASc) and bleeding (HASBLED) Warfarin Cmplete warfarin referral prfrma as per lcal prcedures Mnitring and fllw up by Lcal AC services Decisin made t anticagulate Referrer t indicate Warfarin r NOAC (taking int cnsideratin NCL NOAC criteria*) Warfarin remains the current standard f treatment acrss NCL. Nte that all referral prfrmas will be reviewed by the haematlgist t ensure apprpriateness; referrer may be cntacted NOAC Cmplete NOAC referral prfrma as per lcal prcedures Rivarxaban is preferred NCL agent. Dabigatran / apixaban can be used where clinically justified Existing AC patients fulfilling NCL NOAC criteria: Refer back t AC clinic fr review NCL NOAC criteria* 1. Alpecia, rash etc with n ther cause 2. Significant technical difficulties with INR mnitring r accessing the AC clinic; husebund patients, where INR mnitring r clinic attendance wuld adversely affect quality f life / raise safety cncerns. Nte: cnsider alternatives such as cmmunity AC services, dmiciliary mnitring, review f medicines management and selftesting 3. Prprtin f patient-time in range f < 65% nce AC established (nt due t wilful nn-cmpliance); INR 8.0 n 1 ccasin r INR > 5.0 n 2 ccasins ver a perid f 6 mths (nce A/C established), with a high likelihd f recurrence; VKA supply issues (e.g. phenindine) 4. Unlicensed indicatin, shrt term use nly f dabigatran by individual centres. If AC required lng term pst DCCV (regardless f rhythm), then switch t warfarin unless NCL criteria applicable 5. Lcally designated cnsultants in Strke medicine, thrmbsis r cardilgy NCL NOAC criteria* summary (refer t pints 1-5 fr further explanatin) Dcumented warfarin/vka allergy r specific intlerance 1 Unable t cmply with warfarin/vka specific mnitring requirements 2 Unable t achieve satisfactry INR cntrl 3 Awaiting DCCV r urgent AF ablatin (within 4 weeks) 4 Specific clinical indicatin as advised by lcally designated cnsultants 5 Nn-cmpliance is NOT a reasn t switch t NOAC Primary care Cmplete NOAC referral prfrma Secndary care Rutine utpatients r inpatients: letter t GP requesting referral t lcal AC clinic Nn NCL patient: refer back t GP fr lcal pathway Secndary care Urgent utpatients r inpatients: direct referral t patient s lcal AC clinic fr OP initiatin; cmplete NOAC referral prfrma Nn NCL Secndary care anticagulatin (AC) clinic Select apprpriate NOAC and dse Cunsel and initiate treatment Review fr tlerance and adherence at ne mnth; issue secnd mnth s prescriptin Transfer care t GP with apprpriate paperwrk; GP t take ver frm start f mnth 3 NB: referral pathways may be subject t lcal variatin Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

10 Appendix 2: Risk assessment with CHA 2 DS 2 -VASC and HAS-BLED scring systems (AF patients) CHA 2 DS 2 -VASC scre fr AF patients Cmpared t the lder CHADS 2 scre, the CHA 2 DS 2 -VASc scre 5 is able t discriminate thse patients wh are truly at lw risk frm AF (i.e. CHA 2 DS 2 -VASc = 0, which is essentially patients <65years with lne AF and n additinal risk factrs). Fr these patients, n antithrmbtic therapy is generally the preferred ptin. Patients with ne r mre risk factrs (i.e. CHA 2 DS 2 -VASc scre f > 1, but excluding female sex), shuld be cnsidered fr anticagulatin. Risk Factr Scre C Cngestive heart failure / LV dysfunctin < 40% 1 H Hypertensin 1 A 2 Age > 75 years 2 D Diabetes Mellitus 1 S 2 Strke / TIA/ Systemic emblism 2 V Vascular disease (e.g. prir MI, peripheral artery 1 disease, artic plaque) A Age years 1 Sc Sex categry (i.e. female) 1 Maximum scre 9 CHA 2DS 2- VASc scre Adjusted strke rate (%/year) 0 0% 1 1.3% 2 2.2% 3 3.2% 4 4.0% 5 6.7% 6 9.8% % Ref 5 HAS-BLED scre (validated fr AF patients) The risk f bleeding shuld be assessed befre starting anticagulatin and at least annually (with the annual review f AF). The HAS-BLED scring system 6 has been validated as a practical tl that can be used t assess the bleeding risk in patients with AF and can therefre supprt the clinical decisin making prcess regarding antithrmbtic therapy. Risk Factr Scre H Hypertensin (systlic BP > 160mmHg) 1 A Abnrmal renal and liver functin (1 pint each) 1 r 2 Abnrmal renal functin: chrnic dialysis, renal transplantatin r serum Cr > 200µml/L Abnrmal liver functin: chrnic hepatic disease (e.g. cirrhsis) r bichemical evidence f significant hepatic derangement (e.g. bilirubin > 2 x upper limit f nrmal in assciatin with AST/ALT/ALP > 3x upper limit f nrmal) S Strke 1 B Bleeding (previus bleeding histry and/r 1 predispsitin t bleeding e.g. bleeding diathesis, anaemia etc) L Labile INR s (unstable/high INR s r pr time in 1 therapeutic range e.g. < 60%) E Elderly (e.g. age > 65years) 1 D Drugs (i.e. medicatins) r alchl (1 pint each) 1 r 2 e.g. cncmitant use f antiplatelets, NSAIDs, r alchl abuse Maximum scre 9 HAS- BLED scre Majr bleed s per 100 pt years Insufficient data Ref 6 A HAS-BLED scre f > 3 indicates that the patient is at high risk f bleeding and sme cautin and regular review f the patient is required fllwing the initiatin f antithrmbtic therapy. Effrts shuld be made t crrect ptentially reversible risk factrs fr bleeding. A high HAS-BLED scre per se, shuld nt be used t exclude patients frm anticagulant therapy. References 5. Lip et al. Chest 2010; 137(2): Pisters R et al. Chest 2010; 138: Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

11 Appendix 3: Cckcrft & Gault (C&G) frmula The creatinine clearance (CrCL ml/min) as estimated using the C&G frmula, is the parameter mst ften used in clinical trials and by drug manufacturers t determine dse adjustments fr renally eliminated medicatins. There are inherent inaccuracies hwever when the C&G frmula is used t estimate CrCL in certain patient ppulatins i.e. the very elderly, thse with lw bdy weight, very high bdy weight, reduced muscle mass r with pr nutritinal status. Cautin is therefre advised when using C&G t estimate renal functin fr these patient grups, and dsing advice shuld be sught as apprpriate frm the lcal anticagulatin teams. Cckcrft and Gault frmula 7 (C&G) in μml/l Estimated CrCL (ml/min) = (140 age) x weight*(kg) [x 1.23 if male] r [x 1.04 if female] serum creatinine (µml/l) CrCl is creatinine clearance (ml/min) crrected fr bdy weight *Calculate weight as fllws (steps 1 and 2) 1. Estimate ideal bdy weight 8 (IBW) kg Males: IBW = 50 kg kg fr each inch ver 5 feet Females: IBW = 45.5 kg kg fr each inch ver 5 feet 2. Cmpare IBW t patient s ttal bdy weight (TBW) kg (as measured using weighing scales) a. If TBW is 120% r less f the IBW then use TBW in the C&G frmula b. If TBW is mre than 120% f the IBW, then calculate the adjusted bdy weight (ABW) 8 kg, and use ABW in the C&G frmula Adjusted bdy weight (ABW) = IBW x (TBW-IBW) References 7. Cckcrft DW and Gault H. Nephrn 1976;16: Basic Clinical Pharmackinetics 4th editin; Michael Winter. Editr: DB Try. Lippinctt Williams& Wilkins, Philadelphia Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

12 Trust lg Appendix 4: Rivarxaban cunselling recrd (file/scan in medical ntes) Hspital Number: Patient Name: Date f Birth: This patient has been cunselled n the fllwing areas f rivarxaban therapy, by a dctr, pharmacist r Anticagulant clinical nurse specialist in accrdance with the guidance verleaf Cunselling pint 1. Indicatin fr rivarxaban 2. Alternative anticagulatin ptins 3. Benefits and disadvantages f rivarxaban cmpared t warfarin 4. Expected duratin f therapy (specify if knwn) 5. Basic mde f actin 6. Dse 7. Hw t take: Must be taken with fd t imprve amunt absrbed Aim t take at the same time f day 8. What t d if a dse is missed: If taking 20mg (r 15mg) OD: Take ne tablet as sn as it is remembered and then take the next tablet the fllwing day (and cntinue). D nt take tw tablets in ne day t make up fr the missed dse If taking 15mg BD (e.g. acute VTE): take ne tablet as sn as remembered. D nt take mre than tw 15mg tabs in a single day (but can take 2 tablets at the same time t make a ttal f 30mg n ne day). Cntinue with ne 15mg tablet BD n the next day Extra dse taken accidentally? Cntact dctr r healthcare team 9. Imprtance f cmpliance: Fairly rapid fall in drug levels (and therefre lss f efficacy) if prly cmpliant Ways f remembering t take the tablets e.g. calendar 10. Mnitring (e.g. renal functin) and hw ften Signature Cmments 11. Side effects f rivarxaban (and what t d if experienced) Signs/symptms f excess anticagulatin: bleeding r bruising Recurrence f thrmbemblism (if relevant) 12. Ptential fr drug interactins: paracetaml is the preferred analgesic 13. Alchl intake 14. Cntraceptin, pregnancy, and hrmne replacement therapy (if relevant) 15. Surgical prcedures (inc. day surgery /dental treatment & hspital admissin) 16. Hbbies and leisure activities (including flying) 17. Injectins (including immunisatin) infrm nurse that pt is anticagulated 18. Hw t btain further supplies f rivarxaban 19. Wh t cntact fr advice/ further infrmatin The patient must receive a rivarxaban patient infrmatin bklet and patient alert card. The alert card MUST be fully cmpleted and the patient advised t keep it with him/her at all times Cunselled by: (Sign & print name):... Bleep / Extn:...Date:.. Patient s signature: Date:.. Rivarxaban strke and systemic emblism preventin in nn-valvular AF; practical guidance fr NCL

13 Rivarxaban Cunselling Guidelines Prvide patient with the Xarelt patient infrmatin bklet and g thrugh it with him/her, ensuring that the pints belw are cvered. Cmplete the patient alert card -if unsure f any sectins, check with the dctr. The patient alert card shuld be kept with the patient at all times. 1. Indicatin: licensed fr: (a) Preventin f strke and systemic emblism in adult patients with nn-valvular AF with additinal risk factrs (b) Treatment f DVT/PE (c) preventin f recurrent DVT/PE in adults. 2. Alternative anticagulants: warfarin (and ther ral vitamin K antagnists), lw mlecular weight heparin (e.g. dalteparin), ther newer ral anticagulants (e.g. dabigatran, apixaban). Fr AF, rivarxaban was shwn t be as effective as warfarin fr the preventin f strke and systemic emblism, with a similar rate f majr bleeding, but with a lwer risk f intracranial haemrrhage. There was a higher rate f GI bleeding, epistaxis and haematuria with rivarxaban cmpared t warfarin. Fr the treatment f acute DVT /PE: rivarxaban was shwn t be as effective as warfarin (plus initial SC enxaparin) in preventing symptmatic recurrent VTE, with a similar (DVT trial) r lwer (PE trial) rate f majr bleeding. 3. Advantages (vs. warfarin): fixed dse, n rutine cagulatin mnitring, mre stable anticagulatin cntrl, lwer risk f intracranial haemrrhage (AF pts); Disadvantages (vs. warfarin): unable t rutinely mnitr cagulatin, nt as easy t reverse cmpared t warfarin (n frmal drug antidte), limited lng-term data 4. Expected duratin f therapy if unsure, check with Dctr. 5. Basic mde f actin: belngs t a grup f medicines called antithrmbtic agents; blcks a bld cltting factr (factr Xa) and thus reduces the tendency f the bld t frm clts. 6. Dse: Nn-valvular AF: 20mg OD*; Acute VTE: 15mg BD fr 3 wks, then 20mg OD*. *review dse if CrCL 15-49mL/min see SPC 7. Hw t take: Fr rivarxaban dses > 15mg, the dse must be taken with fd t imprve absrptin; aim t take at the same time each day. 9. Cmpliance: Rivarxaban has a shrter half-life than warfarin and efficacy mre likely t be affected if prly cmpliant. 10. Mnitring: the dse will need t be reduced / stpped if renal functin deterirates. Frequency f mnitring depends n the level f renal functin and may vary frm minimum 3mnthly t 6-12mnthly. Als, FBC and LFTs, minimum annually 11. Side effects f rivarxaban (and what t d if experienced) Fr VTE patients: recurrence f thrmbemblism: cntact dctr if riginal symptms recur Bldy stls r urine, nse bleeds (lasting fr > 5-10mins r if pt des nt usually suffer frm nse bleeds), bld sht eye, cughing r vmiting bld, severe r spntaneus bruising, unusual headaches, excessive vaginal bleeding, cuts that take lnger than 5 minutes t stp bleeding. Seek medical attentin. If invlved in majr trauma, suffer a significant blw t the head r are unable t stp bleeding seek immediate medical attentin Any ther side-effects: discuss with GP r anticagulant clinic 12. Ptential fr drug interactins: may be affected by sme medicines / herbal preparatins (see SPC fr Xarelt ). Therefre: Patient shuld always let dctr/dentist/pharmacist knw that s/he is n rivarxaban Nt t take aspirin unless prescribed by dctr, as increased risk f bleeding (- cmbinatin t be reviewed; will need GI prtectin). Avid OTC painkillers such as ibuprfen, aspirin, diclfenac etc (paracetaml is preferred) If admitted t hspital, t infrm staff that s/he is taking a new ral anticagulant (t avid duplicatin f therapy with standard VTE thrmbprphylaxis). 13. Alchl intake: alchl is nt expected t affect rivarxaban levels per se. Hwever, excess alchl cnsumptin and binge drinking are generally nt advised fr anticagulated patients, due t the risks f alchl assciated acute injuries (e.g. head injuries) and chrnic liver disease (which may affect cagulatin). 14. Cntraceptin, pregnancy, and hrmne replacement therapy (if relevant): Wmen shuld nt becme pregnant nr breast feed whilst taking rivarxaban. Reliable cntraceptin is required. If patient is currently taking HRT/OCP then discussins are required regarding stpping r apprpriate chice (generally avid estrgen-cntaining preparatins; prgesterne nly nes are preferred). Fr wmen taking rivarxaban wh may be pregnant, discussin with the Haemstasis SpR is required ASAP s that pt can be seen by a haematlgist / bstetrician fr discussin re ptential implicatins. If planning t becme pregnant, then pt shuld discuss with GP fr nward referral t a haematlgist. 15. Surgical prcedures (including dental treatment) and hspital admissin: patient must infrm healthcare prfessinal that s/he is taking rivarxaban especially as (1) patient will need management f anticagulatin arund prcedures and (2) VTE thrmbprphylaxis (e.g. LMWH) is ften prescribed n admissin t hspital. 16. Hbbies and leisure activities: avid cntact sprts (e.g. bxing) and ther higher risk sprts (e.g. skiing and hrse riding), as increased risk f bruising/bleeding. Infrm Dr/anticagulant clinic if flying in the near future. 18. Obtain further supplies f rivarxaban frm the hspital (r GP nce care transferred). Nt t run ut f supplies, especially when n hliday. 19. Further advice/inf frm lcal A/C clinic, GP, Hspital pharmacy medicines inf dept r in an emergency, A&E dept 13