Guidelines for the use of existing and New Oral Anticoagulants (NOAC) in the management of Non-Valvular Atrial Fibrillation (AF)

Transcription

1 Guidelines for the use of existing and New Oral Anticoagulants (NOAC) in the management of Non-Valvular Atrial Fibrillation (AF) July 14 Version 1 September 2012 Updated to v1.1 due to new contraindication for Dabigatran (March 13) Updated to v1.2 following the introduction of Apixaban (August 13) Updated to v1.2.1 following the introduction MHRA alert on contraindications (October 13) Updated to v1.2.2 following a change in the GMMMG website address ( July 14) Full review due September 14 Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 1

2 Contents Page Summary 3 Atrial Fibrillation 4 Background to AF 4 Stroke risk in AF 4 Assessment of need for anticoagulation 5 Lower risk scores 5 Anticoagulant therapy guidance 6 Supporting proper use of the NOACs 7 Patient Counselling 8 Record of Initiation Document to appear in the patients clinical record 9 Comparison of NOACs with warfarin 10 Information for the patient to support informed consent 15 Patient counselling prior to initiation 16 Vitamin K to NOAC transfers 17 Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 2

3 Summary The New Oral Anti-Coagulants (NOACs) are a recent innovation and NHS Stockport Clinical Commissioning Group (NHS Stockport CCG) has approved their use for any indication covered by a NICE Technology Appraisal (TA), provided that the prerequisite criteria specified within the TA is met. Use following hip or knee replacement (TA 245, TA157 & TA170) is provided as a course of treatment by the treating surgeon and so should not need to be prescribed in Primary Care. Separate guidance will be made available for venous thromboembolism once local pathways are reviewed. Currently only Rivaroxaban is licensed for use following acute deep vein thrombosis (DVT) to prevent further DVT or pulmonary embolism (PE)(TA 261) and to treat PE and venous thrombotic events (TA 287). For use in non-valvular atrial fibrillation (AF) Greater Manchester Medicines Management Group (GMMMG) has issued a local position statement which we support. (NICE TA 249, TA 256, TA275). click here. It is important for patient safety, improved patient outcomes and NHS budgets to ensure they are used appropriately, safely and effectively, again GMMMG have produced an algorithm to support decision making click here. Commissioners anticipate that this guidance will be followed and use of NOACs is only permitted at NHS expense within Stockport for NICE approved indications and within the license of the drug used. Tools have been developed to document each initiation and these should form part of the clinical record in both primary and secondary care (Appendix 1). Any use of a NOAC outside its licensed and NICE approved indications will require prior approval and should not be advocated or initiated before such approval has been granted by NHS Stockport CCG. Given the potential safety issues for these new agents, see MHRA guidance click here, their black triangle status (drugs subject to intense monitoring) and the lack of manufacturer support for unlicensed use, NHS Stockport has decided to implement systems which will closely monitor initiation in both primary and secondary care. Secondary care will initiate within this framework for inpatients and agreed that for outpatients the GP should be involved in the decision making as they are responsible for their patients long term health. Where a consultant feels a patient may benefit from a NOAC they will write to the patients GP suggesting a NOAC be tried, giving the full rationale for this and a suggestion of the licensed agent to be tried. Locally warfarin is likely to remain the preferred option for most patients. Patients should only need to be switched from Vitamin K antagonists where they are compliant but are unable to tolerate the chosen antagonist or fail to remain within the appropriate INR range. This overview guidance document details the basic considerations but with so many variables it cannot be comprehensive. Advice on individual cases can however be provided by your prescribing adviser or by contacting the confidential encrypted prescribing enquiry e- mail service at STOCCG.-Pxenquiries@nhs.net. Alternatively you can always speak to your practice prescribing adviser or the medicines optimisation office on We also have access to advice from consultants at SFT (Stockport NHS Foundation Trust) should it be a clinical issue rather than a pharmaceutical one. Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 3

4 Atrial Fibrillation (AF) Background to AF AF is a relatively common phenomenon occurring in 1-2% of patients and being more common in older people. The condition carries a 5-6 times higher risk of stroke compared to patients in sinus rhythm and leads to 12,500 strokes a year nationally. The key strategy to prevent stroke is proper anticoagulation. Until recently the only truly effective treatment was a Vitamin K antagonist but recently three new drugs have come to the market and offer some benefits over warfarin e.g. in a lower risk of intracranial bleed, but may also have some drawbacks e.g. lack of safety data in long term use or in providing lower protection against MI. This guidance aims to help and support clinicians in making decisions about the need and safety of anticoagulation and about the choice of agent to use given the complexity of drug selection dependent on indication, age, renal and liver function. Stroke risk in AF In one year for every 100 people with AF it is expected that 5 will suffer a stroke. The risk varies dependent on age, sex, prior stroke etc (see Assessment section). Strokes which occur in people with AF tend to be more severe than those from other causes and anticoagulants help reduce the risks. Giving a Vitamin K antagonist e.g. warfarin will prevent 3 of those 5 strokes, using Rivaroxaban, Apixaban or Dabigatran 110mg will prevent the same number; only Dabigatran 150mg has shown a small added benefit but with a risk of additional side effects. So in order to prevent 1 stroke we need to spend an additional 77,900 per year on Dabigatran 150mg and not every patient can tolerate or is suitable for this higher dose. Cost incurred using other strengths or lower doses will not prevent additional strokes but my provide anticoagulation with a slight reduction in frequency of the rare adverse event, intracranial bleed. The overall bleeding risk with anticoagulants is the same No treatment treated with a Vitamin K antagonist Treated with 150mg Dabigatran Annual treatment cost 0 Annual treatment cost < 100 Annual treatment cost 78,000 Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 4

5 The NICE TAs assumed a testing cost in excess of 500 per annum per patient which is greatly in excess of the local cost and therefore the cost effectiveness analysis performed by NICE should be applied with some caution. Currently in excess of 4,000 patients within Stockport have a diagnosis of AF and the vast majority tolerate warfarin very well and remain within therapeutic range most of the time making the use of NOACs for everyone prohibitively expensive for the benefit offered. It is therefore essential these drugs are only initiated where there is a clearly stated benefit e.g. Vitamin K antagonists cannot be used. Not every patient can be treated with an anticoagulant so proper assessment of need and risk is essential. Assessment of need for anticoagulation The tools to assess the need for anticoagulation are widely available for clinicians to use and many clinical systems incorporate them. The initial step is to undertake assessment and identify if patient needs and is suitable for anticoagulation. The local Cardiac Network advised use of CHADS2 or CHA 2 DS 2 -VASc and HAS-BLED. The GRASP-AF tool can also be helpful and will help identify the group of patients diagnosed with AF but not currently taking an anticoagulant and the tool should be run annually as patient risk factors will change over time. CHADS2 is suitable as an initial assessment tool but is thought to underestimate the risk in some people; therefore the CHA 2 DS 2 -VASc tool was developed to give a more accurate assessment. If result 2 using CHADS2 or CHA2DS2-VASC tools then anticoagulation is indicated provided the patient is not at high risk of bleeding. Bleeding risk needs to be assessed and considered once the need for anticoagulation has been completed (consider completing a HAS-BLED score to assess the risk of bleeding). For CHADS2 scores less than 2 the more specific CHA 2 DS 2 -VASc tool must be used. Lower risk scores CHA2DS2-VASC Score of 1 The annual risk in this group is 1.3% and a patient stabilised on warfarin will have an absolute risk of 1% and so patients should be tried on warfarin 1 st line. 1 st line medication can be started by referral to the local anticoagulant service. However women with no other risk factors score 1. In younger women the risk is low but increases with age, it therefore seems unreasonable to treat below the age of 60 in the absence of other risks. CHA2DS2-VASC Score of 0 Don t treat. Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 5

6 Anticoagulant therapy guidance Once assessment of the need and suitability for anticoagulation has been assessed, the offer of treatment should be on the basis of an agreement between the treating clinician and patient on what is best for them. Whilst patient preference should be considered the clinician must be in agreement as to what is the best course of treatment for their patient. The anticipated pathway would be Vitamin K antagonist e.g. warfarin or acenocoumarol (Sinthrome ). Patients currently on a Vitamin K antagonist who are stable and in range should be maintained on this drug alternatively consider a NOAC but only if AF is non-valvular, the specific NICE TA criteria are met and drugs not contra-indicated. As these drugs are new to market, the full, long-term side effects of their use are not yet fully known. Any side effects should be reported using the yellow card system. On this basis, the use of these drugs should be introduced with careful supervision and patients should be monitored closely. Concern with these drugs also includes a lack of known reversibility of the anticoagulation in those patients who present with major bleeding. A table of comparison between anticoagulants is included in Appendix 2 to support clinicians in making decisions on whether an NOAC should be used. Please note the MHRA now advise that impaired renal function may constitute a contraindication, recommendation not to use or require dose reduction for any of the three NOACs. See MHRA guidance click here and refer to the SPC for the specific drug under consideration. NOACs are appropriate for patients tried on warfarin but where There has been more than two episodes of High INR (>5) within the last year without an obvious cause e.g. concomitant antibiotic use or The patient has experienced significant and intolerable side effects on warfarin and/ or acenocoumarol (Sinthrome ) or The time in therapeutic range (TTR) is less than 65% during 6 months of use after the initial dose titration phase (TTR can be calculated using the Rosendaal method by anticoagulant service on request). Use of any anticoagulant requires that the patient is fully counselled on the benefits and risks of use and that they give fully informed consent. This process is normally completed by the anticoagulant clinic when initiating a Vitamin K antagonist but MUST be completed by the initiating clinician for the NOACs. (See patient counselling and consent). Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 6

7 Anticoagulation of any type is contraindicated where the patient has recent brain or spinal injury including intracranial haemorrhage recent brain, spinal or opthalmic surgery a history of injurious falls (i.e. one resulting in laceration requiring suture, fracture or dislocation) but not non injurious falls current or recent gastrointestinal ulceration other active bleeding including malignant neoplasm or a lesion which is at risk of bleeding known or suspected oesophageal varices atriovenous malformation, vascular aneurysm or intracerebrovascular abnormality uncontrolled hypertension (control hypertension and then review) unsafe alcohol consumption (binge drinking) The HAS-BLED tool can be used to assess bleeding risks. Wafarin and acenocoumarol remain the standard treatment for the majority of patients and should be considered wherever possible. A side effect or problem with one does not necessarily preclude the use of the other and clinicians should decide whether one or the other would provide control or avoid side effects. A safe process for transfer from either of these drugs to the NOACs is being piloted through secondary care and details of how to transfer between agents will be sent out once this is in place. In the interim NO patient should be switched to the NOACs outside of a hospital setting without support from colleagues at SFT. Please contact the Medicines Optimisation office to request this as necessary. Supporting proper use of NOACs The NHS Stockport Clinical Policy Group agreed that additional assurance and surveillance was necessary for these new agents as in the early days following the launch of the NOACs many enquiries for advice on their use were for unlicensed indications or for situations where the use of NOACs was not NICE approved, e.g. Apixaban in valvular AF, Dabigatran for PE prevention etc. There were also failings in checking renal function prior to initiation, failure to allow for interacting drugs and inappropriate dose selection. The Group has Grey Listed all the NOAC drugs, restricting their use to licensed, NICE approved indications. Any use outside this requires prior approval by NHS Stockport CCG through a Grey List Approval Request. This applies equally to initiation in either primary or secondary care. Both primary and secondary care are to ensure all initiations are appropriately documented in the clinical record (see Appendix 1) and these records will be reviewed by Medicines Optimisation on a regular basis to ensure no patient is put at risk. This process will be required until clinicians become familiar with their use, a robust system to transfer between groups is established and until commissioners are confident that these new drugs are being used safely, appropriately and effectively across the health economy. Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 7

8 Patient counselling Patients should be fully counselled in order to ensure informed consent; this will take some time to do so when considering suggesting a NOAC to a patient it will be necessary to allow an extended appointment to fully cover the required information. A counselling guide and supporting patient information leaflets have been developed to support clinicians through this process (see page 15). Without informed consent the clinician is open medico-legally and given the issues which are emerging with these drugs we would strongly recommend that patient counselling and consent are documented in the clinical record. Patients could be asked to sign consent to say they have been fully counselled and that they wish to start the medication if a clinician wishes to do this. It is vital that all patients are followed up after a few weeks to ensure the key counselling has been remembered and that the drug is proving suitable. Thereafter only an annual review is needed with the necessary blood tests. All patients starting oral anticoagulants should be encouraged to take advantage of the new medicines service available from many community pharmacies so additional advice and support can be provided. Counselling and continual reinforcement is particularly important with the NOACs as patients will not get the regular reminder of risks from their attendance at the anticoagulant service. During trials the patients will have had continued support which is likely to have ensured better compliance than is seen by patients taking their medication routinely. It is widely recognised that up to 50% of patients may not take their medication as prescribed and the implications of this for the NOACs must be recognised. Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 8

9 Record of initiation of Newer Oral Anticoagulants(NOAC s) -please file in patients notes Medication will not be issued by SHH Pharmacy Dept without a fully completed request form Patient s Name GP Name & Practice DOB NHS number Address I confirm that use is within the NICE Approved licensed indications and confirm that the patient does not have any of the following (tick to confirm each point has been considered) Any contraindication to taking the medication A history of injurious falls e.g. fracture, dislocation or laceration requiring suture Active bleeding e.g. wounds, lesions or active peptic ulceration Uncontrolled hypertension Alcohol consumption outside of normal limits A history of poor or non-compliance with anticoagulants or current medication I confirm that: The patient has been fully counselled, has been given the patient information leaflet and has agreed to take the medication. The patient does not have valvular AF Please tick indication for use please note, not to be used in Valvular AF Non-valvular AF with one or more of the risk factors shown below -Please indicate chosen NOAC, tick relevant boxes to show that patient fulfils NICE criteria and indicate which dosage has been prescribed. Dabigatran Rivaroxaban Apixaban Criteria Dose Previous stroke, TIA or systemic embolism Left ventricular ejection fraction below 40% Symptomatic HF of NYHA II or above Age >75 years of age Age >65 years with one of the following Diabetes mellitus Coronary artery disease Controlled Hypertension Dosage prescribed (please tick) Dabigratran 110mg BD Patients aged 80 and above Interacting drugs e.g verapamil High bleeding risk, or low thrombosis risk <50kg Moderate renal impairment. N.B Dabigatran is contraindicated in severe renal impairment CrCL < 30ml/min Dabigatran 150mg BD Prescribers Signature Print Name:- Congestive HF Hypertension Age >75years Diabetes mellitus Prior stroke or TIA Dosage prescribed (please tick) Rivaroxaban 15mg daily CrCl ml/min Rivaroxaban 20mg daily Congestive HF Hypertension Age >75years Diabetes mellitus Prior stroke or TIA Dosage prescribed(please tick) Apixaban 2.5mg BD Used in patients with at least 2 of the following- aged 80 or above, serum Cr of 133 or more, weight less 60kg. N.B Apixaban is contraindicated in patients with CrCl<15ml/min or undergoing dialysis Apixaban 5mg BD Date For SHH pharmacy use;- For Stockport Patients Only:- Give to pharmacy office to send to Stockport Medicines Management Office For all non Stockport Patients:- photocopy of NOAC Form to be posted with discharge letter to GP do not send to Stockport Medicines Management Office Information reviewed and approved by SHH pharmacist Print pharmacists name Date Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 9

10 Comparison of New Oral Anticoagulants with Warfarin - Information for Prescribers How does it work? What is the evidence? Warfarin Dabigatran Rivaroxaban Apixaban Effects multiple steps of the clotting cascade using compounds made with Vitamin K by the liver. It s effects can be reversed by giving Vitamin K In a meta-analysis 1, the relative risk reduction (RRR) with warfarin was highly significant and amounted to 64%, corresponding to an absolute annual risk reduction in all strokes of 2.7%. When only ischaemic strokes were considered, adjusteddose VKA use was associated with a 67% RRR. This reduction was similar for both primary and secondary prevention and for both disabling and non disabling strokes. It is estimated that untreated, 5 in every 100 patients with AF will suffer a stroke. Warfarin use will prevent 3 of these A direct thrombin (factor IIa) inhibitor. The prodrug, dabigatran etexilate, is converted to the active drug dabigatran after administration 2. The drug can be dialysed 9 from the blood but there is currently no antidote to reverse its effects. The serious consequences of the lack of an effective reversal agent should not be underestimated. Prolonged bleeding has increased morbidity & possibly contributed to deaths 4 The RE-LY study 3 of 18,113 patients. 50% of patients were naïve to oral anticoagulants. It was a prospective, open-label, blinded endpoint (PROBE) design. Dabigatran 150mg BD reduced the annual absolute risk of stroke or systemic embolism by 0.6% cf with warfarin (35% RRR) & by 0.43% (10% RRR) compared with dabigatran 110mg BD. Compared with warfarin, Dabigatran 150mg will prevent 4 of the 5 predicted strokes /100 patients, 110mg will prevent 3. Both haemorrhagic and ischaemic stroke occurred less often in the dabigatran 150mg BD group than with warfarin. Dabigatran was non-inferior to warfarin. Compared with warfarin, dabigatran significantly reduced the incidence of haemorrhagic, but not ischaemic stroke. Patients with bleeding risks were excluded from RE-LY A selective direct factor Xa inhibitor. Inhibition of Factor Xa interrupts the blood coagulation cascade, inhibiting thrombin formation & development of thrombi 10. There is currently no antidote to its effects but prothrombin complex concentrate has been successful in showing normalisation of clotting times (APTT & thrombin times) in a small preliminary trial 12 ROCKET-AF 11 was a double-blind, double dummy randomized trial that of 14,264 patients to either rivaroxaban 20mg daily or warfarin with an INR 2-3. Patients were moderate to high risk of stroke (CHADS2 >2). Patients received 20mg od (15mg od if CrCl 30-49mls/min) or warfarin (appropriate dose). Rivaroxaban was non-inferior to warfarin for stroke prevention & systemic embolism in both the perprotocol and intention-to-treat (ITT) analysis. In the ITT analysis 2.1 events per 100 patient-years were seen in the rivaroxaban group cf.to 2.4 events with warfarin (HR 0.88, 95% CI 0.75to 1.03, p<0.001). Superiority testing did not reach statistical significance. In the ITT population 30% of outcome events in the rivaroxaban arm occurred after discontinuation of treatment, cf. with 22% of events in the warfarin arm. A possible rebound effect, which may be related to the short half-life (5-13 hrs) A selective direct factor Xa inhibitor. It interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting thrombin formation It indirectly inhibits platelet aggregation induced by thrombin. There is currently no antidote though trials are ongoing ARISTOTLE 13 was a double-blind, RCT of 18,201 patients on either 5mg bd (2.5mg bd in selected patients (4.7% of trial patients )) or warfarin with an INR target range of 2-3 (time in range 66% ave.) for a mean of 22 months. Apixaban was non-inferior to warfarin for the prevention of stroke and systemic embolism in the intention-to-treat (ITT) population and was later shown to be superior. The primary outcome (ischaemic or haemorrhagic stroke or systemic embolism) occurred in 212 patients in the apixaban group compared to 265 with warfarin (rate of primary outcome hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66 to 0.95, p<0.001 for non-inferiority and p=0.01 for superiority). The rate of the primary outcome was 1.27% per year compared with 1.6% per year for warfarin Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 10

11 Dose and dynamics Oral tablet in 1, 3, & 5mg strengths but 1mg tablets are advised by MHRA. Variable dose dependent on INR taken daily. Due to long half-life and persistent effects, warfarin is tolerant of delayed doses or occasional missed dose. May be included in a dosette if patients dose is stable at the discretion of the dispensing pharmacy Oral capsule in 150mg and 110mg - taken within 18 hours of previous dose to maintain protection. (See SPC). Half-life approx. 12 hours hence need for bd dose Patients under 80 years -150mg bd Patients >80 years -110mg bd (due to an increased risk of bleeding) Reduce to 110 mg bd in patients taking interacting drugs (see SPC) Consider 110 mg bd when there is a low risk of thromboembolism and the bleeding risk is high 2 or patients weigh <50kg Do not use if CrCl is below 30ml/min Not stable for use in dosette Oral tablet in 20 & 15mg- taken at a similar time each day (see SPC if dose missed). Usually 20mg od 10 but reduce to 15mg od when CrCl is 15-49ml/min 10. Extra caution is required if CrCl is 15-29mls/min due to an increased bleeding risk 10 May be stable for use in dosette Oral tablet- doses should be taken at similar times each day (see SPC if dose missed). Half-life approx. 12 hours hence need for bd dose Usual dose 5mg bd for prophylaxis of stroke reduced to 2.5mg bd if 2 or more of the following >80 years old or a body weight of 60kg or less or renal impairment (see SPC for details.) May be stable for use in a dosette. Monitoring Dose needs to be adjusted to the individual needs of the patient based on regular INR testing to keep patient in therapeutic range. Outside the target range, risk of stroke if low or risk of haemorrhage if high increases significantly. INR monitoring not required and not helpful. Trials show a predictable response at usual doses when taken correctly. Renal function should be assessed (calculate CrCl) in all patients before starting and at least annually or id a decline in renal function is suspected 5. A high number of cases of serious and fatal haemorrhage have been reported globally in elderly patients with renal impairment who were receiving dabigatran. Availability in three strengths which have predictable effects means that the drug does not need the same level of monitoring as warfarin. Available in two strengths with predictable effects so INR monitoring not required Safety Long-term safety based on 50 years use in clinical practice. Caution over use in thrombophilia - patients with C or S protein deficiency. No information available on long-term safety. Cannot be used if CrCl <30mls/min Caution in hepatic impairment- liver enzymes >2 times upper normal limit should not receive dabigatran Use with caution in conditions with an increased bleeding risk No information available on long-term safety CrCl 15-49mls/min a reduced dose is recommended mg can be used Cannot be used if CrCl<15ml/min Caution in hepatic impairment No information available on long term safety. Cannot be used if CrCl<15ml/min. CrCl ml/min should receive the apixaban 2.5 mg bd. Caution in mild to moderate hepatic impairment. Not for use in severe hepatic impairment. Limited data on use in patients at the extremes of bodyweight. 14 Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 11

12 Bleeding compared to warfarin See respective agent for comparison RE-LY 3 showed major bleeding rates for warfarin & dabigatran 150mg bd however, major bleeding was lower with dabigatran 110mg BD than with warfarin. The incidence of GI bleeding was significantly higher with dabigatran 150mg bd (p=0.0008), than in patients treated with warfarin but similar with dabigatran 110mg bd (p=0.52)intracranial bleeding was uncommon for any anticoagulant but higher with warfarin than Dabigatran 150mg bd or 110mg bd (RR0,76% vs. 0.32% or 0.23% respectively, p <0.001).A recent audit of bleeding events with dabigatran highlighted that frail, elderly patients particularly with renal impairment and low body weight are at risk of increased bleeds 4 ROCKET-AF 11 showed:- No significant difference in major or non-major clinically relevant bleeding GI bleeding was more common with rivaroxaban than warfarin (3.2% vs.2.2%, p=<0.001), as were a decrease in Hb of >2g/dl (4.3% vs. 3.6%, p=0.02), need for transfusion (2.6% vs. 2.1%, p=0.04), epistaxis (10.1% vs. 8.6%, p<0.05), and haematuria (4.2% vs. 3.4%, p<0.05) Intracranial haemorrhage was less common with rivaroxaban than warfarin (0.8% vs. 1.2%, p=0.02), as were critical bleeding (1.3% vs. 1.9%, p=0.007) and fatal bleeding (0.4% vs. 0.8%, p=0.003) ARISTOTLE showed fewer bleeding events for all major bleed types (intracranial HR 0.42, 95% CI 0.30 to 0.58; other major bleeding HR 0.79, 95% CI 0.68 to 0.93) & clinically relevant bleeding events apart from major GI bleed, which was not statistically significant (HR 0.89, 95% CI 0.70 to 1.15, p=0.37). Major bleed event rate 2.13% for Apixaban 3.09% for warfarin (HR % CI ) or 4.07% per year for apixaban vs. 6.01% per year on warfarin for major or clinically relevant non-major bleeding (HR 0.68, 95% CI 0.61 to 0.75, p<0.001) Side effects Rashes can commonly occur. Other side effects can include hair loss A higher rate of dyspepsia occurred at any dose of dabigatran compared with warfarin. GI adverse events led to drug discontinuation rates being significantly higher (7%, 6.5% and 3.9% in the dabigatran 150mg, 110mg and warfarin groups respectively) 3. Caution and surveillance will therefore be needed with pre-existing GI problems there was a nonsignificant increase in the number of myocardial infarctions (MI) in patients taking dabigatran compared to warfarin (0.82% for 110mg and 0.81% for 150mg vs. 0.64% p=0.12) 3,6,7 A meta-analysis 8 combining 7 studies showed dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group. The control group varied and included enoxaparin, warfarin and placebo 8. There were no significant differences in the incidence of any other adverse event other than bleeding in ROCKET- AF 10 (81% with rivaroxaban vs. 82% of warfarin patients). The most frequently reported adverse events in the rivaroxaban group were epistaxis (10%), peripheral oedema (6.1%) and dizziness (6.1%), and in the warfarin group were epistaxis (8.6%), nasopharyngitis (6.4%) and dizziness (6.3%). The rate of MI was numerically, but not statistically, significantly lower in the rivaroxaban arm compared with the warfarin group 11 Bleeding is common 24.3% in studies including epistaxis, contusion, haematuria, haematoma, eye haemorrhage, and gastrointestinal haemorrhage 15 Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 12

13 Interactions See SPC for full details as information can change Drug specific contraindications See SPC for full details as information can change Drug-food interactions Cranberry juice and alcohol interact with warfarin. Some foods interact with warfarin (e.g. foods containing high amounts of Vitamin K). Drug-drug interactions Many interactions requiring additional INR monitoring or which may prevent concurrent use. See reference text for details Within 72 hours of major surgery with risk of severe bleeding. Within 48 hours postpartum Pregnancy (first and third trimesters) Drug-food interactions 2 Currently there are no known food interactions. Drug-drug interactions Special care when prescribing with any drug that may increase bleeding risk e.g. NSAIDs antiplatelets SSRIs and SNRIs increased the risk of bleeding in all treatment groups. No effect on cytochrome P450, so the potential for cytochrome P450 drug-drug interactions is low. There is a potential for P-gp interactions e.g. amiodarone, verapamil, quinidine, ketoconazole, clarithromycin, rifampicin, phenytoin and carbamazepine. Please see online SPC for full details of interactions. Concomitant treatment with systemic and ketoconazole, cyclosporine, itraconazole and tacrolimus is C/I. Consult the SPC for full details Severe renal impairment (CrCL < 30 ml/min) Spontaneous or pharmacological impairment of haemostasis Hepatic impairment or liver disease expected to have an impact on survival Pregnancy and breastfeeding 2 Concomitant treatment with other anticoagulant (unfractionated or low molecular weight heparin, or heparin derivatives unless switching between anticoagulants under supervision. Dronedarone Patients with prosthetic heart valves Drug-food interactions 10 Currently there are no known food interactions. Drug-drug interactions 10 Not recommended with concomitant systemic treatment with azoleantimycotics e.g. ketoconazole, itraconazole, voriconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp. Strong CYP3A4 inducers should be coadministered with caution (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) as they may lead to reduced rivaroxaban concentrations. For full details of interactions consult the SPC. Hypersensitivity to any of the excipients or active substance. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Pregnancy and breast feeding CrCl <15mls/min 10 Concomitant treatment with other anticoagulant unfractionated or low molecular weight heparin, or heparin derivatives unless switching between anticoagulants under supervision. Drug-food interactions Currently there are no known food interactions. Drug-Drug interactions Not to be prescribed with the following drugs: Systemic azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) HIV protease inhibitors (e.g., ritonavir) Caution with inducers/inhibitors of both CYP3A4 and P-gp (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort, diltiazem, amiodarone, verapamil) as this may lead to reduced efficacy of apixaban and a higher risk of bleeding. Caution with NSAIDs, aspirin, other antiplatelets and antithrombotic agents. Hypersensitivity to any of the excipients or active substance CrCl <15ml/min) or undergoing dialysis. breast feeding (caution in pregnancy) Hepatic disease associated with coagulopathy Concomitant treatment with other anticoagulant agent unfractionated or low molecular weight heparin, or heparin derivatives unless switching between anticoagulants under supervision. When should it be used in AF First line for any patient requiring anticoagulants Within the parameters of the NICE TA for non-valvular AF and its SPC particularly when warfarin and/or acenocoumarol are not tolerated. Within the parameters of the NICE TA for non-valvular AF and its SPC particularly when warfarin and/or acenocoumarol are not tolerated. Within the parameters of the NICE TA for non-valvular AF and its SPC particularly when warfarin and/or acenocoumarol are not tolerated. Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 13

14 When should it be avoided? Intolerance e.g. allergy, or side effects likely to result in discontinuation (other than bleeding complications) e.g. severe alopecia Acenocoumarol is often a suitable alternative in these patients. Demonstrated impossibility of monitoring or achieving warfarin control e.g. due to long term interacting drug therapy (INR persistently and significantly above or below range that does not respond to dose titration) AVOID dabigatran in patients with a history of poor medication adherence. AVOID in patients with severe renal impairment CrCl <30mls/min AVOID in patients with liver disease or severe hepatic impairment Dabigatran is not a suitable alternative to warfarin in patients with bleeding complications associated with warfarin treatment, contraindications to warfarin therapy due to a high bleeding risk, alcohol abuse, drug overdose or trivial side effects related to warfarin. Dabigatran is also contraindicated in patients with prosthetic heart valves AVOID rivaroxaban in patients with a history of poor medication adherence. AVOID in patients with CrCl <15mls/min and use with caution if CrCl15-29mls/min. AVOID in patients w i t h liver disease or severe hepatic impairment. Rivaroxaban is not a suitable alternative to warfarin in patients with bleeding complications associated with warfarin treatment, contraindications to warfarin therapy due to a high bleeding risk, alcohol abuse, drug overdose or trivial side effects related to warfarin. AVOID apixaban in patients with a history of poor medication adherence. AVOID in patients with CrCl <15mls/min and use lower dose if CrCl 15-29mls/min. AVOID in patients with liver disease or severe hepatic impairment. Apixaban is not a suitable alternative to warfarin in patients with bleeding complications associated with warfarin treatment, contraindications to warfarin therapy due to a high bleeding risk, alcohol abuse, drug overdose or trivial side effects related to warfarin. This information is a summary to guide prescribers and subject to change Please consult individual SPCs for further information at References 1. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146: SPC Pradaxa. Accessed march Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: Harper P, Young L, Merriman E. Bleeding Risk with Dabigatran in the Frail Elderly. N Engl J Med 2012; 366: Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363: Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY trial. Circulation 2012; DOI: /?CIRCULATIONAHA Available at: 8. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; DOI: /archinternmed Available at: 9. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet Apr;49(4): SPC Xarelto 20mg. Accessed march Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011;365: Eerenberg ES et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate. Circulation 2011; 124: Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2011;365(11): SIGN 129. Antithrombotics: indications and management 15. SPC apixaban (Eliquis) Bristol Myers-Squibb Review Date: September 2013 (does the review date need changing)? Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 14

15 Information for the patient to support informed consent Advise patients of the benefits compared to Vitamin K antagonists Protection against stroke which is at least as good as the Vitamin K antagonists No need for monitoring required other than annual blood tests Some agents have lower bleeding risks for major bleed Advise on the risks compared to warfarin We have years of experience with warfarin and many, many people are well controlled The possibility of interactions with other medications bought over the counter or prescribed such as aspirin and other anti-inflammatories are known for warfarin, we know some interactions for the NOACs but more are being found and the drugs remain black triangle because of this Dabigatran gives less protection against heart attacks than warfarin does The overall bleeding risk is the same as with warfarin, intracranial haemorrhages occur less often but GI bleeds can be common If relevant Advise on effective contraception and ask them to inform GP if they believe they may be pregnant. Bleeding Bleeding is a common side effect e.g. nose bleeds. Inform patients that they may bleed more easily or may bleed longer while taking an oral anticoagulant. Unlike warfarin, the effects of these new anticoagulants CANNOT easily be reversed. Hospitals are putting in place special plans to manage patients on these agents who are admitted with excessive bleeding e.g. after an accident. Instruct patients to seek emergency care right away if they have any of the following, which may be a sign or symptom of serious bleeding: Unusual bruising (bruises that appear without known cause or that get bigger) Pink or brown urine Red or black, tarry stools Coughing up blood Vomiting blood, or vomit that looks like coffee grounds Instruct patients to call their health care provider or to get prompt medical attention if they experience any signs or symptoms of bleeding: Pain, swelling or discomfort in a joint Headaches, dizziness, or weakness Reoccurring nose bleeds Unusual bleeding from gums Bleeding from a cut that takes a long time to stop Menstrual bleeding or vaginal bleeding that is heavier than normal Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 15

16 Gastrointestinal Adverse Reactions Instruct patients to tell you if they experience any new signs or symptoms of dyspepsia or gastritis such as burning, nausea, abdominal or epigastric pain or discomfort or if preexisting symptoms significantly worsen. Diarrhoea may also occur. Patient counselling prior to initiation If patient is currently taking a Vitamin K antagonist Inform patient of process to switch from a Vitamin K antagonist to the new drug and ensure that they keep taking warfarin until told not to. (See transfer process information) For all patients Tell patients how to take it. These drugs need to be taken regularly as unlike warfarin protection is lost within a few hours of a missed dose (see drug and indication specific guidance below) Take with or without food, it makes no significant difference If an extra capsule is accidentally taken the patient should seek medical advice Remind patients not to discontinue medication without talking to the health care provider who prescribed it Ensure the patient is aware that they should tell other healthcare professionals they take an anticoagulant including their doctor, dentist and pharmacist The patient should be advised to report all suspected interactions to their doctor, pharmacist or directly to the MHRA themselves Patient should be asked to ensure they are provided with an alert card by the pharmacy that dispenses their medication. They should be told to carry this with them at all times and this could be checked whenever the patient is reviewed. Patient should also be advised to take advantage of the New Medicines Support service available through many pharmacies. Specific information for Patients taking Dabigatran. Patient Information Leaflet for use of Dabigatran in AF click here The dose is usually one capsule twice a day and the capsules stored at room temperature Doses should be taken at roughly the same times each day or if forgotten as soon as they remember provided it is more than 6 hours until the next dose. If it is less than 6 hours to the next dose omit the dose and take the next one as normal. Tell patients to keep the capsules in the original pack to protect from moisture and not put them in pill boxes or pill organizers. Advise patients not to chew or break the capsules before swallowing them and not to open the capsules and take the pellets alone. Specific information for Patients taking Rivaroxaban Patient leaflet for use of Rivaroxaban in AF click here Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 16

17 The dose is taken once daily at roughly the same time. If a dose is missed it should be taken as soon as remembered and the next dose taken as normal provided this is not on the same day. Specific information for Patients taking Apixaban Patient leaflet for use of Apixaban in AF click here If a dose is missed take apixaban as soon as remembered and then continue with twice daily doses as before. Vitamin K to NOAC transfers Medicines Optimisation advice should be sought if you are in any doubt about this process Changeovers will initially be managed by Dr Malik at SFT regardless of where the patient usually attends for anticoagulant monitoring until we are sure that we have developed a safe transfer process. The Process 1. The decision is made to transfer a patient over to a NOAC. 2. The record of initiation is completed and faxed to Medicines Optimisation on The patient should continue to take Vitamin K antagonist until told to stop by SFT. 4. The patient s GP should add the new medication on to the patient s record as an acute item but NOT issue any to the patient at this time. 5. Medicines Optimisation verify that all the necessary details have been supplied and fax it to SFT 6. SFT contact the patient and invite them to attend for an initial appointment with cardiology. The patient is reviewed to ensure the dose and drug are appropriate for them and a blood sample is taken. Any issues identified will be communicated to the practice. 7. Dependent on the blood result the patient may be a. Given an initial 7 day supply of the NOAC and told to take no more warfarin and start taking the NOAC immediately b. Given an initial 7 day supply of the NOAC and told to stop the warfarin and start the NOAC the next day c. Asked to stop taking the Vitamin K antagonist and attend SFT again, this may be the next day or up to 3 days later for another blood sample. 8. Daily INR testing may be necessary to ensure a safe changeover as the INR must be under specific levels to start the new drug. 9. Once transferred Dr Malik will write to you with details of the transfer. Trying to change anticoagulants without following the proper process may lead to significant bleeding or a blood clot and is not recommended. Other Trusts are using other processes but we do not support any other process locally at this time. Guidelines for the use of new and existing oral anticoagulants v1.2.2 Page 17