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RIVAROXABAN for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation: supporting practical guidance for primary care (NCL Joint Formulary Committee website – NOAC - http://ncl-jfc.org.uk/noac-prescribing-guides.html) 1.0 Introduction: indication and licensing 1 NICE TA 256 recommended rivaroxaban (Xarelto®) as an option for the prevention of stroke and systemic embolism within its licensed indication i.e. in adult patients with non-valvular atrial fibrillation with one or more risk factors such as: • congestive heart failure • hypertension • age ≥ 75 years • diabetes mellitus • prior stroke or transient ischaemic attack 2 Rivaroxaban is an orally active direct Anti-Xa inhibitor. ROCKET-AF was a large, prospective, randomised controlled trial in over 14,000 patients with CHADS2 score > 2 that compared rivaroxaban to adjusted dose warfarin (INR range 2.0 to 3.0). Patients with CrCL < 30mL/min as estimated by Cockcroft & Gault were excluded from the trial. The primary efficacy outcome was the composite of stroke (ischemic or hemorrhagic) and systemic embolism whilst the principal safety end point was a composite of major and non-major clinically relevant bleeding events. ROCKET-AF demonstrated non inferiority with in the primary endpoint (composite of ischaemic or haemorrhagic stroke and systemic emboli) with incidences of 1.7% per-100 patient years in the rivaroxaban arm versus 2.2% in the warfarin arm; p < 0.001. Major and non-major clinically relevant bleeding was not significantly different between the two groups. Intracranial haemorrhage occurred less often with rivaroxaban (0.5% versus 0.7%, HR 0.67; 95% CI 0.47 to 0.93; P = 0.02), as did fatal bleeding (0.2% per year vs. 0.5% per year, P = 0.003). Major GI bleeding was more common with rivaroxaban (3.2%) than with warfarin (2.2%, P<0.001), as were bleeds requiring transfusion (1.6% per year for rivaroxaban vs 1.3% per year for warfarin; p=0.04). 2.0 Use across North Central London (NCL) The new oral anticoagulants (NOAC) such as rivaroxaban, dabigatran and apixaban, are all NICE approved and are considered alternatives to warfarin (currently standard treatment) for the prevention of stroke and systemic embolism in patients diagnosed with non-valvular AF, with CHA2DS2VASc > 1 (excluding female gender) and assuming that NCL criteria are fulfilled (summarised in table below). Rivaroxaban is the preferred agent as per the NCL Joint Formulary Committee, although dabigatran or apixaban can be used where clinically justified NCL criteria Known allergy / intolerance to warfarin or other vitamin K antagonist Significant technical difficulties with INR monitoring and/or accessing A/C clinic that raises safety concerns Patient-time in range < 65% once established on warfarin (not due to wilful non-compliance). Comments e.g. alopecia with no other cause (such as iron deficiency anaemia, hypothyroidism etc) Consider alternatives such as community A/C services, domiciliary monitoring/input or self-testing Non-compliance is not a reason to switch to NOAC. Consider alternatives such as community A/C services, domiciliary monitoring/input or self-testing INR ≥ 8.0 on 1 occasion or INR > 5.0 on 2 occasions over a period of 6 months (once A/C is established), with a high likelihood of recurrence (i.e. unsafe) Phenindione supply issues Awaiting DC-cardioversion or urgent AF ablation within 4 weeks [dabigatran only] Dabigatran is the only NOAC currently licensed for DC-cardioversion. All NOAC are unlicensed for AF ablation. If ongoing anticoagulation required post procedure (regardless of rhythm), then switch to warfarin unless any of the other criteria listed in this table are fulfilled. Specific clinical indication as per locally designated consultant in stroke medicine / thrombosis / cardiology Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 1 3.0 Patient pathway – an overview (See appendix 1 for complete AF NOAC pathway) Governance structures are required to ensure the safe and robust introduction of NOAC into routine clinical practice. The use of secondary care anticoagulation clinics would fulfil this requirement and is the model agreed by NCL for initiation of NOAC. Decision to anticoagulate and NOAC criteria fulfilled GP*refers pt to local AC clinic using NOAC referral proforma Hospital AC clinic initiates, prescribes and monitors NOAC for 2 months** After 2 months, GP takes over prescribing & monitoring GP to re-refer to local A/C clinic if needed *If urgent, then secondary care can directly refer patients to his/her local AC clinic for outpatient initiation ** Referral pathways may be subject to local variation, but the minimum requirements are outlined above 4.0 Roles and Responsibilities 4.1 Referring clinician to: • Calculate CHA2DS2VASc score (see appendix 2) • Risk assess patient for anticoagulation (including the HAS-BLED score – see appendix 2) • Check routine biochemistry (FBC, U&E, LFT), calculate CrCL (using Cockcroft & Gault equation, appendix 3), check coagulation screen and blood pressure • Confirm that NOAC is appropriate, in line with NCL guidance • Discuss risks vs. benefits of anticoagulation with the patient • Complete the NOAC referral proforma and refer patient to his/her local anticoagulation clinic for NOAC counselling and initiation • For patients identified in secondary care requiring anticoagulation for AF: o Outpatients: GP to refer to local anticoagulation clinic o Outpatient stroke neurologists/physicians, or designated cardiologists/haematologists may refer patient to his/her local A/C clinic directly in cases where urgent anticoagulation is required (as is done currently); these patients may be on a low molecular weight heparin as an interim measure o Inpatients: If urgent, IP team to refer to patient’s local anticoagulation clinic for OP initiation. Otherwise, patient to be referred to the local anticoagulation clinic by GP • In general, NOACs should only be initiated by secondary care anticoagulation clinics, to ensure that robust governance processes will be followed 4.2 Anticoagulation (A/C) clinic to: • Check baseline bloods as per normal practice: FBC, U&E, LFTs, coagulation screen (if not on A/C) or INR (if on warfarin) • Select appropriate NOAC after review of clinical data provided on referral proforma (rivaroxaban is the preferred agent as per the NCL Joint Formulary Committee, although dabigatran or apixaban can be used where clinically justified) • Scan referral proforma into electronic records (or file in medical notes if former not possible) • Deliver standardised verbal counselling as per NCL/local checklist (patient to sign) • Provide (1) written information about the drug and (2) a patient alert card (available from the drug company) • Arrange an initial supply of 4 weeks (month 1) and provide a follow-up A/C clinic appointment within 4 weeks • Inform GP (standard NCL letter) that patient has been initiated on NOAC • Review the patient within 4 weeks to assess tolerability and compliance. Assuming no concerns, arrange the second month's prescription (NB: if there are concerns, clinic to liaise with referring clinician / local haematologist) • After the second visit (when month 2’s prescription is issued) and assuming that patient will remain on NOAC, immediately inform GP via standard transfer of care letter (fax and phone to confirm receipt of information) to ensure continuity of care and NOAC supply • GP should aim to take over care as from the start of month 3. A/C clinic to ensure that GP agreement has been received (and scanned onto electronic records or the equivalent) before discharging patient from the clinic • Ensure patient understands the transfer process and how to obtain further supplies • Enter details on local A/C database Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 2 4.3 GP responsibilities • As per points listed under 4.1 if referring the patient Also: • Update GP practice records, detailing that NOAC has been initiated (with months 1 and 2 being supplied by secondary care) • During month 2 of treatment, sign the transfer of care form to confirm agreement for ongoing prescribing and monitoring as from the start of month 3, and fax back to the anticoagulation clinic • Reiterate the importance of patient compliance and review on a regular basis to avoid accidental stoppage. Reiterate the need to carry the patient alert card at all times • Undertake appropriate clinical monitoring (section 11.0) and be aware of possible drug interactions • Notify other healthcare professionals if patient is to undergo any invasive treatments (e.g. dental or elective surgery) • Undertake an annual review regarding the ongoing appropriateness of anticoagulation, including a review of the cautions and contraindications to rivaroxaban • Refer back to the local anticoagulation clinic if there are any clinical concerns 5.0 Contraindications and exclusion criteria to rivaroxaban In October 2013, the MHRA strengthened the contraindications for all NOACs (dabigatran, rivaroxaban and 3a apixaban) . Patients listed in the categories below, should not receive rivaroxaban. Contraindications / exclusions to use (not exhaustive – refer to Xarelto® SPC3) Lesion or condition, if considered to be a significant risk factor for major bleeding. This may include: • Current/recent upper or lower GI ulceration; oesophageal varices (known or suspected); malignant neoplasms at high risk of bleeding • Surgery/trauma or bleed affecting head/brain, eyes or spine within last 4 weeks • AV malformations, vascular aneurysms or major intraspinal / intracerebral vascular abnormalities • Stroke in last 14 days/severe stroke in last 6 months (unless advised by designated stroke neurology cons) • Uncontrolled hypertension (systolic BP > 180mmHg and/or diastolic BP > 100mmHg), vascular retinopathy • Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C • CrCL < 15mL/min (calculated as per C&G formula) Pregnancy and lactation (crosses placenta and into breast milk) Indications not covered by licence e.g. prosthetic heart valve(s) requiring anticoagulation; INR range higher than 2.0-3.0 required Contraindicated: concomitant treatment with other anticoagulants, except when switching to or from rivaroxaban (as advised by A/C clinic, haematology SpR or haemostasis consultant), or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter Not recommended: systemic ketoconazole, itraconazole, posaconazole, voriconazole, HIV protease inhibitors Avoid: dronedarone 6.0 Cautions Patients falling into the following categories should be discussed with the local haematologist. Cautions to use (not exhaustive – refer to Xarelto® SPC3) History of previous major bleed on anticoagulation / antiplatelet therapy Thrombocytopenia (e.g. platelets < 75) Abnormal baseline coagulation screen (repeat and investigate before initiation of NOAC) Weight < 50 kg or > 120kg Abnormal liver function tests (2 x upper limit of normal) Myeloproliferative disease / sickle sell disease (limited evidence on use) Congenital or acquired bleeding disorders 3 Antiplatelets, NSAIDs, rifampicin, phenytoin, phenobarbitone, carbamazepine, St John’s Wort – refer to SPC and table 2 Age > 75 years; discuss with local haematologist if additional risk factors for bleeding Excessive alcohol intake High risk of recurrent falls resulting in significant injury Patients < 18 years (unlicensed – discuss with haematologist) Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 3 Note: the concomitant use of aspirin or other antiplatelets with rivaroxaban significantly increases the risk of major bleeding. All antiplatelet (and NSAID) use must be reviewed prior to initiating rivaroxaban. See sections 7.0 and 8.0 7.0 Dose and administration • • • • • • • • The standard licensed dose of rivaroxaban for AF is 20mg OD (15mg OD in specific circumstances – see below) CAUTION: the 10mg rivaroxaban tablet is licensed for VTE thromboprophylaxis in elective hip or knee replacement surgery. Please ensure that only the 15mg/20mg strength tablets are prescribed or dispensed for AF, to minimise drug errors and patient confusion Note that plasma levels and excretion of rivaroxaban are affected by many variables including renal function and drug interactions – see below for further information and for advice re dose adjustments Rivaroxaban must be taken with food to maximise bioavailability Both the 20mg and the 15mg tablets are film-coated, but are not modified or controlled release. Crushing the tablets for patients who are unable to swallow would not be expected to affect the release characteristics per se, but would make it an unlicensed administration method (clinical decision and responsibility) If a dose is missed, then the patient should take rivaroxaban as soon as it is remembered (- local practice at UCLH is to limit this to within 8 hours). Continue with the next dose the following day as usual. The dose should not be doubled within the same day to make up for a missed dose The tablets can be dispensed into medication reminder devices if appropriate Formulation contains lactose: avoid in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption Table 1: Rivaroxaban dosing for specific patient groups Usual standard dose for AF: Rivaroxaban 20mg OD Plasma levels and excretion of rivaroxaban can be affected by many variables including renal function and drug interactions. If there are a number of risk factors for bleeding, then reconsider the overall risk vs benefit of treatment with rivaroxaban Risk factors for bleeding with rivaroxaban Rivaroxaban dosing comments (refer to SPC3) HAS-BLED score > 3 and where anticoagulation is appropriate Consider 15mg OD in line with recommendations from The 4 European Society of Cardiology (ESC) History of gastritis, oesophagitis or gastro-oesophageal reflux disease and where anticoagulation is appropriate Low bodyweight (e.g. < 50kg) Increased risk of major GI bleeding compared to VKA If rivaroxaban appropriate, then PPI cover advised. Renal impairment* CrCL 15-49mL/min Reduce dose to 15mg OD (SPC for AF) (NB: limited clinical data with CrCL 15-29mL/min; plasma concentrations significantly ↑) Do NOT use rivaroxaban (SPC) Renal impairment* CrCL < 15mL/min Antiplatelet agents NSAIDS SSRIs (Selective Serotonin Re-uptake Inhibitors) / SNRIs (Selective Norepinephrine Re-uptake Inhibitors) Certain drug interactions *estimated CrCL using C&G formula (appendix 3) Limited data available - discuss with local haematologist Concomitant use of antiplatelet agents increases the risk of major bleeding - see table 2 for further information Increased risk of bleeding - see table 2 May increase risk of bleeding – see table 2 See table 2 Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 4 8.0 Drug interactions with rivaroxaban3 Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. It is also a substrate of the transporter proteins P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) • Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent, than those strongly inhibiting both pathways 3 Table 2: Drug interactions with rivaroxaban (NB: list is NOT exhaustive) 3 3 Drugs (examples) Effect (SPC ) with examples Action (SPC ) • Systemic azole antimycotics, such as: ketoconazole itraconazole voriconazole posaconazole (These are strong inhibitors of both CYP3A4 and P-gp pathways) HIV protease inhibitors e.g. ritonavir (Strong inhibitor of both CYP3A4 and P-gp pathways) Dronedarone Potent CYP3A4 and moderate P-gp inhibitors e.g. clarithromycin / telithromycin) Strong CYP3A4 inducers Rifampicin Phenytoin Carbamazepine Phenobarbitone St. John's Wort (Hypericum perforatum) Anticoagulants such as unfractionated heparin, LMWH (dalteparin, enoxaparin etc), fondaparinux, other oral anticoagulants (warfarin, dabigatran, apixaban etc) Thrombolytic agents, GPIIb/IIIa inhibitors ↑ rivaroxaban plasma concentrations expected, leading to increased risk of bleeding Ketoconazole ↑ AUC (2.6 fold) and ↑ Cmax (1.7 fold) NB: fluconazole is a moderate CYP3A4 inhibitor and its interaction with rivaroxaban is not considered to be clinically relevant ↑ rivaroxaban plasma concentrations expected, leading to increased risk of bleeding Ritonavir ↑ AUC (2.5 fold) and ↑ Cmax (1.6 fold) Limited available clinical data Possible ↑ plasma concentration in patients with renal impairment (from pharmacokinetic modelling studies) ↓ rivaroxaban plasma concentrations expected. Rifampicin ↓mean AUC of rivaroxaban by approximately 50 %. Other strong CYP3A4 inducers (examples given), may also lead to ↓ rivaroxaban plasma concentrations. Increased risk of major bleeding Increased risk of major bleeding Aspirin / clopidogrel Increased risk of major bleeding Other antiplatelet agents (e.g. Ticlodipine / prasugrel / ticagrelor) NSAIDs Likely increased risk of major bleeding SSRIs (Selective serotonin reuptake inhibitors) / SNRIs (selective norepinephrine re-uptake inhibitors) Concomitant use is not recommended Increased risk of bleeding May increase risk of GI bleeding Concomitant use is not recommended Avoid concomitant use Use with caution Use with caution Combination contraindicated, except when switching therapy to or from rivaroxaban (as advised by A/C clinic / haemostasis SpR or Consultant), or when unfractionated heparin is given at doses necessary to maintain a patent central venous or arterial catheter Interaction not specifically mentioned in the SPC, but advise avoid combination – d/w haemostasis consultant should the situation arise Stop antiplatelet agents UNLESS another specific clinical indication (other than AF) exists. If concomitant therapy unavoidable (and a careful risk-benefit assessment has been made) then review the most appropriate drug combination. PPI cover advised. Close clinical monitoring required Interaction not specifically mentioned in SPC; combination not recommended Avoid if at all possible. Careful risk-benefit assessment required. If benefit of chronic NSAID outweighs risk of bleeding, then PPI cover advised. Close clinical monitoring required Interaction not specifically mentioned in the SPC - use with caution. If other risk factors for bleeding present, then consider GI cover; close clinical monitoring required Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 5 9.0 Converting from VKA or low molecular weight heparin (LMWH) to rivaroxaban Secondary care anticoagulation clinics will switch patients to rivaroxaban. GPs should not do this please. 3 Recommendations from the SPC are outlined below for information only: Vitamin K Antagonist (VKA e.g. warfarin) to rivaroxaban • Stop warfarin 3 • Start rivaroxaban when the INR is < 3.0 (NB: a different recommendation exists for VTE patients – refer to SPC ) LMWH to rivaroxaban i.e. patients on longterm therapeutic dose LMWH being switched to rivaroxaban. (For anticoagulation around elective procedures, refer to section 12.0) • Stop LMWH • Start rivaroxaban 0 to 2 hours before the time of the next scheduled administration of SC LMWH 10.0 Adverse effects • • • • • • As would be expected, rivaroxaban increases the risk of bleeding during treatment and patients should be monitored for signs of bleeding/anaemia Patients should be advised to seek medical advice if persistent or frequent episodes of bleeding occur; he/she should seek urgent medical attention if severe bleeding is experienced. Note that there is currently no pharmacological antidote to rivaroxaban. In case of intolerance to rivaroxaban, patients should be instructed to consult their doctor as soon as possible so that treatment can be reviewed and alternative options considered. Discussion with the local haematology consultant / local anticoagulant clinic is advised 3 Common side effects (≥ 1/100 to < 1/10) as listed in the SPC include: dyspepsia, diarrhoea, nausea, vomiting, hypotension, oedema and dizziness (not exhaustive - refer to the current BNF or SPC for further information) From various phase 3 studies (different indications), mucosal bleeding (e.g. epistaxis, gingival, gastrointestinal, genitourinary) and anaemia were seen more frequently during long term rivaroxaban treatment compared with 3 warfarin/VKA . 2 Specifically from ROCKET-AF : o Rivaroxaban 20mg OD (15mg OD for CrCL 30-49mL/min), resulted in similar rates of major bleeding compared to warfarin (3.6% vs 3.4%, p=0.58). The rate of critical organ bleeding was less with rivaroxaban (0.8% vs 1.2%, p= 0.007), as were both the risk of intracranial haemorrhage (0.5% vs 0.7%, p = 0.02) and the risk of fatal bleeding (0.2% vs 0.5% p=0.003). o Decreases in haemoglobin levels of > 2 g/dL and major bleeding requiring transfusions were more common among rivaroxaban patients, as was major bleeding from a gastrointestinal site (3.2% vs 2.2%, p <0.001). o Epistaxis (10.1% vs 8.6%) and haematuria (4.2% vs 3.4%) occurred more frequently with rivaroxaban than with warfarin (p< 0.05). (All stats quoted as event rate no./100 patient-yr) IMPORTANT: Long-term safety/tolerability is not yet known. These ‘black triangle’ drugs and are being intensively monitored. All suspected adverse drug reactions should be reported to the MHRA either using the BNF ‘yellow card’ system or online at www.mhra.gov.uk/yellowcard Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 6 11.0 Recommended monitoring for rivaroxaban for primary care Monitoring parameter FBC, U&Es, LFTs, blood pressure and HAS-BLED score Comment Prior to referral to local A/C clinic. (NB: these will be reviewed by the anticoagulation team) Thereafter, as clinically indicated (minimum annually) but see below for renal function. Review if LFTs > 2 x upper limit of normal, platelets <100, or uncontrolled hypertension Renal function: once initiated, monitor as suggested in adjacent column (NB: patients > 75 years may require more frequent monitoring) Reassess when decline suspected (e.g. hypovolaemia, dehydration, certain co-medications etc.) est. CrCL (C&G formula) CrCL > 80mL/min Suggested monitoring frequency Annually CrCL 50-79mL/min CrCL 30-49mL/min 6-12 monthly Close monitoring at discretion of clinician (minimum 3 monthly)* Close monitoring at discretion of clinician (minimum 3 monthly)* Do not use CrCL 15-29mL/min CrCL < 15mL/min *dose reduction required for AF: refer to Xarelto SPC Ongoing clinical surveillance, including: 1) Checking to avoid accidental NOAC stoppage 2) Checking for possible interactions with new medicines 3) Reinforcing the importance of carrying the rivaroxaban ‘patient alert’ card at all times Annual clinical review to: 1) Assess the continuing need for antithrombotic therapy 2) Asses the risk vs. benefit of anticoagulation i.e. o History of stroke / TIA o Bleeding risk using the HAS-BLED score, including any bleeding episodes. NB: Routine anticoagulation monitoring is NOT required 3 Throughout the treatment period and in line with general anticoagulation practice Consider whether current dose remains optimal or whether dose reduction / referral back to specialist is required. Standard coagulation parameters (e.g. Activated partial thromboplastin time (APTT) and prothrombin time (PT), may be affected to varying degrees, but do not provide quantitative information on the intensity of anticoagulation effect. 12.0 Management around elective invasive procedures / surgical interventions • • Note that clinical experience with rivaroxaban and bridging around surgical procedures is limited The management of anticoagulation around elective procedures should be in accordance with the appropriate local secondary care management guidelines - liaise with the local haematologist/anticoagulation clinic In general, steps to follow include: • Several weeks pre-op, inform surgeon / other clinician undertaking procedure that patient is taking rivaroxaban for AF. Additional useful information from primary care includes CHA2DS2VASc score and patient’s bleeding history. • Rivaroxaban will need to be stopped at least 24 hours prior to the intervention, depending on renal function / proposed intervention (secondary care to advise). The T1/2 is 5-9 hours in young healthy individuals, increasing 3 to 11-13hours in the elderly . • Post procedure and depending on risks of bleeding vs thrombosis, secondary care may advise initial post-op management with thromboprophylactic doses of LMWH, escalating to therapeutic dose LWMH (or rivaroxaban – see below) when surgeons happy and as per local bridging guidelines. Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 7 • Rivaroxaban to restart when there are no concerns re surgical haemostasis, patient is eating and drinking and reinitiation of therapeutic anticoagulation is appropriate (peak levels usually reached approx 2-4hours post 3 dose with steady state reached within approx 2-3 days with normal renal function). How to switch from LMWH to rivaroxaban (only in the context of management of anticoagulation around elective procedures). For the routine switch from longterm LMWH to new rivaroxaban, refer to section 9.0 o o Stop LMWH Start rivaroxaban approx. 12hrs after last dose of prophylactic LMWH, 12hrs after last dose of therapeutic LMWH if in divided BD dose (e.g. dalteparin 100 units/kg SC BD) or 24hrs after last therapeutic once daily LMWH dose (e.g. dalteparin 200units/kg SC OD). • For minor procedures including dental procedures under LA/GA and at LOW RISK of bleeding: restart therapeutic dose rivaroxaban (preadmission dose) 6hrs post procedure, then 24hrly thereafter. This assumes surgical haemostasis is secured, oral absorption is assured and immediate therapeutic A/C is safe to resume. Peak levels reached 2-4 hrs post dose. Note: If there are concerns re therapeutic anticoagulation, consider prophylactic dose LMWH and d/w local haematologist. • For urgent acute interventions: contact local haematologist for advice. 13.0 Additional NCL information to support this document NCL Joint Formulary Committee website – NOAC - http://ncl-jfc.org.uk/noac-prescribing-guides.html • NCL position statement on the use of NOAC for the prevention of stroke and systemic embolism in patients diagnosed with non-valvular atrial fibrillation at increased risk of stroke (AF) • NCL Summary treatment pathway for Anticoagulation and AF • NOAC referral proforma • GP NOAC notification and transfer of care forms • Guidelines for bleeding (rivaroxaban) - trusts to write local guidelines 14.0 Appendices • • • • Appendix 1: Summary treatment pathway: anticoagulation for the prevention of stroke and systemic embolism in non-valvular AF Appendix 2: Risk assessment: CHA2DS2-VASc and HAS-BLED scoring systems (AF patients) Appendix 3: Cockcroft & Gault (C&G)formula (to estimate CrCL) Appendix 4: Rivaroxaban counselling checklist 15.0 References 1. 2. 3. 3. 4. 5. 6. 7. 8. NICE technology appraisal guidance 256. Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation. May 2012 Patel MR et al. and the ROCKET AF Steering Committee for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation (and supplementary appendix). N Engl J Med 2011; 365: 883-91. (a) MHRA Drug Safety Update 2013; Vol 7 (3). New oral anticoagulants, apixaban (Elquis▼), dabigatran (Pradaxa▼) and rivaroxaban (Xarelto▼): risk of serious haemorrhage – clarified contraindications apply to all three medicines Summary of product Characteristics. Xarelto 20mg & 15mg film coated tablets. Bayer Pharma AG. Date of first authorisation/renewal of authorisation: 30/09/08. Date of revision June 2013. Available from: www.emc.medicines.org.uk Camm AJ et al. 2012 focussed update of the ESC guidelines for the management of atrial fibrillation. Eur. Heart J. 2012. 33: 2719-2747 Lip et al. Refining clinical risk stratification for predicting stroke and thromboembolism in Atrial Fibrillation using a novel risk factor-based approach. The Euro Heart Survey on Atrial Fibrillation. Chest 2010; 137(2):263–272 Pisters R et al. A novel user-friendly score (HAS-BLED) to assess 1 year risk of major bleeding in patients with AF: The Euro heart survey. Chest 2010; 138: 1093-1100 Cockcroft DW and Gault H. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: 31-41. Basic Clinical Pharmacokinetics 4th edition; 2004. Michael Winter. Editor: DB Troy. Lippincott Williams& Wilkins, Philadelphia Document written on behalf of NCL by: • Ms Carolyn Gates, Lead pharmacist, Thrombosis & Anticoagulation, UCLH NHS Foundation Trust • Dr Hannah Cohen, Consultant haematologist, UCLH NHS Foundation Trust Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 8 Appendix 1: Summary treatment pathway: Anticoagulation for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (AF) ALL referrers (primary & secondary care) Risk assess for stroke prevention (CHA2DS2VASc) and bleeding (HASBLED) Warfarin Complete warfarin referral proforma as per local procedures Monitoring and follow up by Local AC services NOAC Decision made to anticoagulate Referrer to indicate Warfarin or NOAC (taking into consideration NCL NOAC criteria*) Warfarin remains the current standard of treatment across NCL. Note that all referral proformas will be reviewed by the haematologist to ensure appropriateness; referrer may be contacted Complete NOAC referral proforma as per local procedures Rivaroxaban is preferred NCL agent. Dabigatran / apixaban can be used where clinically justified NCL NOAC criteria* summary (refer to points 1-5 for further explanation) Existing AC patients fulfilling NCL NOAC criteria: Refer back to AC clinic for review NCL NOAC criteria* 1. Alopecia, rash etc with no other cause 2. Significant technical difficulties with INR monitoring or accessing the AC clinic; housebound patients, where INR monitoring or clinic attendance would adversely affect quality of life / raise safety concerns. Note: consider alternatives such as community AC services, domiciliary monitoring, review of medicines management and selftesting 3. Proportion of patient-time in range of < 65% once AC established (not due to wilful non-compliance); INR ≥ 8.0 on 1 occasion or INR > 5.0 on 2 occasions over a period of 6 mths (once A/C established), with a high likelihood of recurrence; VKA supply issues (e.g. phenindione) 4. Unlicensed indication, short term use only of dabigatran by individual centres. If AC required long term post DCCV (regardless of rhythm), then switch to warfarin unless NCL criteria applicable 5. Locally designated consultants in Stroke medicine, thrombosis or cardiology • • • • • 1 Documented warfarin/VKA allergy or specific intolerance 2 Unable to comply with warfarin/VKA specific monitoring requirements 3 Unable to achieve satisfactory INR control 4 Awaiting DCCV or urgent AF ablation (within 4 weeks) 5 Specific clinical indication as advised by locally designated consultants Non-compliance is NOT a reason to switch to NOAC Primary care Secondary care Secondary care Complete NOAC referral proforma • Routine outpatients or inpatients: letter to GP requesting referral to local AC clinic • Non NCL patient: refer back to GP for local pathway • Urgent outpatients or inpatients: direct referral to patient’s local AC clinic for OP initiation; complete NOAC referral proforma • Non NCL Secondary care anticoagulation (AC) clinic • Select appropriate NOAC and dose • Counsel and initiate treatment • Review for tolerance and adherence at one month; issue second month’s prescription • Transfer care to GP with appropriate paperwork; GP to take over from start of month 3 NB: referral pathways may be subject to local variation Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 9 Appendix 2: Risk assessment with CHA2DS2-VASC and HAS-BLED scoring systems (AF patients) CHA2DS2-VASC score for AF patients 5 Compared to the older CHADS2 score, the CHA2DS2-VASc score is able to discriminate those patients who are truly at ‘low risk’ from AF (i.e. CHA2DS2-VASc = 0, which is essentially patients <65years with lone AF and no additional risk factors). For these patients, no antithrombotic therapy is generally the preferred option. Patients with one or more risk factors (i.e. CHA2DS2-VASc score of > 1, but excluding female sex), should be considered for anticoagulation. Risk Factor C Congestive heart failure / LV dysfunction < 40% H Hypertension A2 Age > 75 years D Diabetes Mellitus S2 Stroke / TIA/ Systemic embolism V Vascular disease (e.g. prior MI, peripheral artery disease, aortic plaque) A Age 65-74 years Sc Sex category (i.e. female) Maximum score Score 1 1 2 1 2 1 1 1 9 CHA2DS2VASc score Adjusted stroke rate (%/year) 0 1 2 3 4 5 6 9 0% 1.3% 2.2% 3.2% 4.0% 6.7% 9.8% 15.2% Ref 5 HAS-BLED score (validated for AF patients) The risk of bleeding should be assessed before starting anticoagulation and at least annually (with the annual review 6 of AF). The HAS-BLED scoring system has been validated as a practical tool that can be used to assess the bleeding risk in patients with AF and can therefore support the clinical decision making process regarding antithrombotic therapy. Risk Factor H Hypertension (systolic BP > 160mmHg) A Abnormal renal and liver function (1 point each) • Abnormal renal function: chronic dialysis, renal transplantation or serum Cr > 200µmol/L • Abnormal liver function: chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin > 2 x upper limit of normal in association with AST/ALT/ALP > 3x upper limit of normal) S Stroke B Bleeding (previous bleeding history and/or predisposition to bleeding e.g. bleeding diathesis, anaemia etc) L Labile INR’s (unstable/high INR’s or poor time in therapeutic range e.g. < 60%) E Elderly (e.g. age > 65years) D Drugs (i.e. medications) or alcohol (1 point each) e.g. concomitant use of antiplatelets, NSAIDs, or alcohol abuse Maximum score Score 1 1 or 2 1 1 HASBLED score Major bleed s per 100 pt years 0 1 2 3 4 5 6-9 1.13 1.02 1.88 3.74 8.70 12.50 Insufficient data Ref 6 1 1 1 or 2 9 A HAS-BLED score of > 3 indicates that the patient is at high risk of bleeding and some caution and regular review of the patient is required following the initiation of antithrombotic therapy. Efforts should be made to correct potentially reversible risk factors for bleeding. A high HAS-BLED score per se, should not be used to exclude patients from anticoagulant therapy. References 5. Lip et al. Chest 2010; 137(2):263–272 6. Pisters R et al. Chest 2010; 138: 1093-1100 Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 10 Appendix 3: Cockcroft & Gault (C&G) formula • • • The creatinine clearance (CrCL mL/min) as estimated using the C&G formula, is the parameter most often used in clinical trials and by drug manufacturers to determine dose adjustments for renally eliminated medications. There are inherent inaccuracies however when the C&G formula is used to estimate CrCL in certain patient populations i.e. the very elderly, those with low body weight, very high body weight, reduced muscle mass or with poor nutritional status. Caution is therefore advised when using C&G to estimate renal function for these patient groups, and dosing advice should be sought as appropriate from the local anticoagulation teams. Cockcroft and Gault formula7 (C&G) in μmol/L Estimated CrCL (mL/min) = (140 – age) x weight*(kg) [x 1.23 if male] or [x 1.04 if female] serum creatinine (µmol/L) CrCl is creatinine clearance (mL/min) corrected for body weight *Calculate weight as follows (steps 1 and 2) 8 1. Estimate ideal body weight (IBW) kg • Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet • Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet 2. Compare IBW to patient’s total body weight (TBW) kg (as measured using weighing scales) a. If TBW is 120% or less of the IBW then use TBW in the C&G formula b. If TBW is more than 120% of the IBW, then calculate the adjusted body 8 weight (ABW) kg, and use ABW in the C&G formula Adjusted body weight (ABW) = IBW + 0.4 x (TBW-IBW) References 7. Cockcroft DW and Gault H. Nephron 1976;16: 31-41. 8. Basic Clinical Pharmacokinetics 4th edition; 2004. Michael Winter. Editor: DB Troy. Lippincott Williams& Wilkins, Philadelphia Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 11 Trust logo Hospital Number: Patient Name: Appendix 4: Rivaroxaban counselling record (file/scan in medical notes) Date of Birth: This patient has been counselled on the following areas of rivaroxaban therapy, by a doctor, pharmacist or Anticoagulant clinical nurse specialist in accordance with the guidance overleaf Counselling point 1. Indication for rivaroxaban 2. Alternative anticoagulation options 3. Benefits and disadvantages of rivaroxaban compared to warfarin 4. Expected duration of therapy (specify if known) 5. Basic mode of action 6. Dose 7. How to take: Signature Comments • Must be taken with food to improve amount absorbed • Aim to take at the same time of day 8. What to do if a dose is missed: • If taking 20mg (or 15mg) OD: Take one tablet as soon as it is remembered and then take the next tablet the following day (and continue). Do not take two tablets in one day to make up for the missed dose • If taking 15mg BD (e.g. acute VTE): take one tablet as soon as remembered. Do not take more than two 15mg tabs in a single day (but can take 2 tablets at the same time to make a total of 30mg on one day). Continue with one 15mg tablet BD on the next day Extra dose taken accidentally? Contact doctor or healthcare team 9. Importance of compliance: 10. • Fairly rapid fall in drug levels (and therefore loss of efficacy) if poorly compliant • Ways of remembering to take the tablets e.g. calendar Monitoring (e.g. renal function) and how often 11. Side effects of rivaroxaban (and what to do if experienced) • Signs/symptoms of excess anticoagulation: bleeding or bruising • Recurrence of thromboembolism (if relevant) 12. Potential for drug interactions: paracetamol is the preferred analgesic 13. Alcohol intake 14. Contraception, pregnancy, and hormone replacement therapy (if relevant) 15. Surgical procedures (inc. day surgery /dental treatment & hospital admission) 16. Hobbies and leisure activities (including flying) 17. Injections (including immunisation) – inform nurse that pt is anticoagulated 18. How to obtain further supplies of rivaroxaban 19. Who to contact for advice/ further information The patient must receive a rivaroxaban patient information booklet and patient alert card. The alert card MUST be fully completed and the patient advised to keep it with him/her at all times Counselled by: (Sign & print name): ............................................................................ Bleep / Extn:…………………..…….Date: …………………….. Patient’s signature: …………….……………………………….……………................................…..…………………………………………..…..… Date:……………………….. Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13 12 Rivaroxaban Counselling Guidelines Provide patient with the Xarelto patient information booklet and go through it with him/her, ensuring that the points below are covered. Complete the patient alert card -if unsure of any sections, check with the doctor. The patient alert card should be kept with the patient at all times. 1. Indication: licensed for: (a) Prevention of stroke and systemic embolism in adult patients with non-valvular AF with additional risk factors (b) Treatment of DVT/PE (c) prevention of recurrent DVT/PE in adults. 2. Alternative anticoagulants: warfarin (and other oral vitamin K antagonists), low molecular weight heparin (e.g. dalteparin), other newer oral anticoagulants (e.g. dabigatran, apixaban). • For AF, rivaroxaban was shown to be as effective as warfarin for the prevention of stroke and systemic embolism, with a similar rate of major bleeding, but with a lower risk of intracranial haemorrhage. There was a higher rate of GI bleeding, epistaxis and haematuria with rivaroxaban compared to warfarin. • For the treatment of acute DVT /PE: rivaroxaban was shown to be as effective as warfarin (plus initial SC enoxaparin) in preventing symptomatic recurrent VTE, with a similar (DVT trial) or lower (PE trial) rate of major bleeding. 3. Advantages (vs. warfarin): fixed dose, no routine coagulation monitoring, more stable anticoagulation control, lower risk of intracranial haemorrhage (AF pts); Disadvantages (vs. warfarin): unable to routinely monitor coagulation, not as easy to reverse compared to warfarin (no formal drug antidote), limited long-term data 4. Expected duration of therapy – if unsure, check with Doctor. 5. Basic mode of action: belongs to a group of medicines called antithrombotic agents; blocks a blood clotting factor (factor Xa) and thus reduces the tendency of the blood to form clots. 6. Dose: Non-valvular AF: 20mg OD*; Acute VTE: 15mg BD for 3 wks, then 20mg OD*. *review dose if CrCL 15 - 49mL/min see SPC 7. How to take: For rivaroxaban doses > 15mg, the dose must be taken with food to improve absorption; aim to take at the same time each day. 9. Compliance: Rivaroxaban has a shorter half-life than warfarin and efficacy more likely to be affected if poorly compliant. 10. Monitoring: the dose will need to be reduced / stopped if renal function deteriorates. Frequency of monitoring depends on the level of renal function and may vary from minimum 3monthly to 6-12monthly. Also, FBC and LFTs, minimum annually 11. Side effects of rivaroxaban (and what to do if experienced) • For VTE patients: recurrence of thromboembolism: contact doctor if original symptoms recur • Bloody stools or urine, nose bleeds (lasting for > 5-10mins or if pt does not usually suffer from nose bleeds), blood shot eye, coughing or vomiting blood, severe or spontaneous bruising, unusual headaches, excessive vaginal bleeding, cuts that take longer than 5 minutes to stop bleeding. Seek medical attention. • If involved in major trauma, suffer a significant blow to the head or are unable to stop bleeding – seek immediate medical attention • Any other side-effects: discuss with GP or anticoagulant clinic 12. Potential for drug interactions: may be affected by some medicines / herbal preparations (see SPC for Xarelto). Therefore: • Patient should always let doctor/dentist/pharmacist know that s/he is on rivaroxaban • Not to take aspirin unless prescribed by doctor, as increased risk of bleeding ( - combination to be reviewed; will need GI protection). Avoid OTC painkillers such as ibuprofen, aspirin, diclofenac etc (paracetamol is preferred) • If admitted to hospital, to inform staff that s/he is taking a new oral anticoagulant (to avoid duplication of therapy with standard VTE thromboprophylaxis). 13. Alcohol intake: alcohol is not expected to affect rivaroxaban levels per se. However, excess alcohol consumption and binge drinking are generally not advised for anticoagulated patients, due to the risks of alcohol associated acute injuries (e.g. head injuries) and chronic liver disease (which may affect coagulation). 14. Contraception, pregnancy, and hormone replacement therapy (if relevant): Women should not become pregnant nor breast feed whilst taking rivaroxaban. Reliable contraception is required. If patient is currently taking HRT/OCP then discussions are required regarding stopping or appropriate choice (generally avoid oestrogen-containing preparations; progesterone only ones are preferred). For women taking rivaroxaban who may be pregnant, discussion with the Haemostasis SpR is required ASAP so that pt can be seen by a haematologist / obstetrician for discussion re potential implications. If planning to become pregnant, then pt should discuss with GP for onward referral to a haematologist. 15. Surgical procedures (including dental treatment) and hospital admission: patient must inform healthcare professional that s/he is taking rivaroxaban especially as (1) patient will need management of anticoagulation around procedures and (2) VTE thromboprophylaxis (e.g. LMWH) is often prescribed on admission to hospital. 16. Hobbies and leisure activities: avoid contact sports (e.g. boxing) and other higher risk sports (e.g. skiing and horse riding), as increased risk of bruising/bleeding. Inform Dr/anticoagulant clinic if flying in the near future. 18. Obtain further supplies of rivaroxaban from the hospital (or GP once care transferred). Not to run out of supplies, especially when on holiday. 19. Further advice/info from local A/C clinic, GP, Hospital pharmacy medicines info dept or in an emergency, A&E dept 13