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Novel anti coagulants

Comparison of oral anticoagulants
Information for prescribers
March 2014
Key factors influencing anticoagulant choice
Monitored Dosage Systems: neither warfarin nor dabigatran is suitable for use in
a compliance aid. Licensing: all NOACs are licensed for prevention of stroke in non-valvular atrial
fibrillation plus at least one additional risk factor. Warfarin is licensed for use  Comparative costs: each of the newer drugs has a considerably higher acquisition
without additional risk factors. cost than warfarin. When the cost of INR monitoring is taken into account, warfarin is likely to remain the least expensive option up-front. Comparative cost- NICE Guidance and Patient choice: The decision about whether to start
effectiveness is not clear. treatment with any NOAC should be made after an informed discussion between the clinician and the person about the risks and benefits of the NOAC compared  Time in therapeutic range: NOACs are likely to be beneficial in patients with INR
with warfarin. For people who are taking warfarin, the potential risks and benefits of regularly outside the therapeutic range despite good adherence to warfarin. Time in switching to a NOAC should be considered in light of their level of international therapeutic range of ≥65% is considered good.8 normalised ratio (INR) control.  INR testing: INR testing with warfarin is time consuming, but provides an
opportunity to monitor adherence and effectiveness. Compliance: NOACs are not a safe option in patients who are unsuitable for
warfarin due to poor compliance or high bleeding risk. Patients prescribed NOACs
Experience: there is a lack of clinician experience of long term use of NOACs.
should have an on-going review of treatment, preferably 3-monthly.1  Acquisition Cost: If a NOAC is preferred and where all other factors are equal the
Risk of haemorrhage: NOACs have a lower risk of catastrophic intra-cerebral
NOAC with the lowest acquisition cost should be chosen haemorrhage but some (rivaroxaban and dabigatran 150mg) have a slightly higher risk of gastrointestinal haemorrhage.2-4  Patients anticoagulated with either warfarin or newer agents should carry a card Reversal: a major concern with the NOACs is the lack of an effective antidote.
This is counterbalanced to some degree by the lower risk of severe haemorrhage
identifying their medication and who to contact in case of emergency related to reported within clinical trials when compared to warfarin. their anticoagulation. A sample EHRA card is .  Acute bleeding: in the event of acute bleeding patients receiving a NOAC may
When might warfarin be the preferred option?
require surgical haemostasis, fluid replacement, or blood products. These may  In patients with a history of GI problems warfarin is the preferred option due to a also be appropriate for those receiving warfarin, in addition to vitamin K. more favourable GI side effect profile, lower rates of GI haemorrhage compared Suggested approaches to the management of bleeding complications are outlined with NOACs, and reversible nature.  In patients with poor medication compliance, warfarin may be the preferred option  Renal function: dose reduction or cessation of the newer drugs may be required
as patients are reviewed regularly. with reduced renal function.  Patients co-administered medication that may inhibit metabolism and potentiate  Frequency of dosing: dabigatran and apixaban require twice daily dosing,
bleeding risk with novel agents (e.g. azole anti fungals, ritonavir) can be more compared to once daily for rivaroxaban and warfarin safely managed on warfarin as the INR may be adjusted accordingly. Patients will  Extremes of BMI: exposure to the NOACs varies by 20-30% at extremes of
still need appropriate dose adjustment of warfarin on commencement or withdrawal bodyweight (<50 kg or >100-120 kg).5-7 Although no dose adjustment is required, of such therapy. this may be problematic given the difficulties in monitoring the therapeutic effects. Active swapping from warfarin to novel agents:
Specific indications: where continuation of anticoagulation therapy up to and
during a planned procedure (e.g. cardioversion, ablation, etc) would be considered Where patients are established on warfarin with a stable INR there is little or no advantageous, a NOAC may be appropriate where patient compliance can be reason to actively swap over to novel agents. Patients who have warfarin-specific reliably confirmed.1 rather than anticoagulant-associated side effects (e.g. alopecia rather than bleeding) could be offered a novel agent. This information is a summary to guide prescribers – for further information please consult individual SPCs at www.medicines.org.uk
Warfarin9
Dabigatran6
Apixaban7
Licensed
Prophylaxis of systemic Prevention of stroke and systemic embolism Prevention of stroke and systemic embolism Prevention of stroke and systemic embolism in indications
embolism in patients with in adult patients with non-valvular atrial in adult patients with non-valvular atrial adult patients with non-valvular atrial fibrillation, rheumatic heart disease and fibrillation with one or more risk factors, such fibrillation with one or more risk factors, such with one or more risk factors, such as: atrial fibril ation.  prior stroke or transient ischaemic attack  prior stroke or transient ischemic attack  congestive heart failure  age ≥ 75 years  heart failure, NYHA class ≥ II  hypertension  hypertension  age ≥ 75 years  age ≥ 75 years  diabetes mellitus  diabetes mellitus, or hypertension  diabetes mellitus  symptomatic heart failure NYHA class ≥ II  prior stroke or transient ischaemic attack Locally-approved -
Approved in North of Tyne for use prior to indications
NICE status
Recommended as an option for the Recommended as an option for the Recommended as an option for preventing prevention of stroke and systemic embolism prevention of stroke and systemic embolism stroke and systemic embolism within its within its licensed indication (as above) within its licensed indication (as above) marketing authorisation (as above) The decision about whether to start The decision about whether to start treatment The decision about whether to start treatment treatment with dabigatran etexilate should be with rivaroxaban should be made after an with apixaban should be made after an informed made after an informed discussion between informed discussion between the clinician and discussion between the clinician and the person the clinician and the person about the risks the person about the risks and benefits of about the risks and benefits of apixaban and benefits of dabigatran etexilate rivaroxaban compared with warfarin. For compared with warfarin, dabigatran etexilate compared with warfarin. For people who are people who are taking warfarin, the potential and rivaroxaban. For people who are taking taking warfarin, the potential risks and risks and benefits of switching to rivaroxaban warfarin, the potential risks and benefits of benefits of switching to dabigatran etexilate should be considered in light of their level of switching to apixaban should be considered in should be considered in light of their level of international normalised ratio (INR) control. light of their level of international normalised international normalised ratio (INR) control. ratio (INR) control. How does it
Warfarin has an effect on Acts as a direct thrombin (factor IIa) inhibitor. Acts as a selective direct factor Xa inhibitor. Inhibits free and clot-bound factor Xa, and several steps of the clotting It is formulated as dabigatran etexilate, a Inhibition of Factor Xa interrupts the intrinsic prothrombinase activity. Prevents thrombin cascade using compounds pro-drug converted to dabigatran after and extrinsic pathway of the blood generation and thrombus development. No made with vitamin K by the liver. administration. coagulation cascade, inhibiting both thrombin direct effects on platelet aggregation, but formation and development of thrombi. indirectly inhibits aggregation induced by thrombin. This information is a summary to guide prescribers – for further information please consult individual SPCs at www.medicines.org.uk. RDTC 2014
Warfarin9
Dabigatran6
v roxaban5
Apixaban7
Variable dose taken once daily  Patients under 80 years: 150 mg twice  20 mg once daily  5 mg twice daily Administration
dependent on INR  15mg once daily if CrCL 15-49 mL/min.  Reduce to 2.5 mg twice daily in patients  Patients >80 years: 110 mg twice daily Use with caution if CrCL is 15-49 mL/min with two or more of the following (due to the increased risk of bleeding in due to an increased bleeding risk. characteristics: this population)  Reduce to 110 mg twice daily in patients Body weight ≤60kg who are taking verapamil Serum creatinine ≥1.5mg/dL (133  Consider 110 mg twice daily when the thromboembolic risk is low and the  2.5 mg twice daily in patients with CrCL 15- bleeding risk is high (e.g. CrCL 30-50 mL/min) or patients weigh <50kg. Monitoring
Needs to be adjusted to the Available in two strengths which have Available in two strengths which have Available in two strengths which have individual needs of the patient predictable effects, meaning that the drug predictable effects, meaning that the drug predictable effects, meaning that the drug does and therefore requires regular does not need the same level of monitoring does not need the same level of monitoring not need the same level of monitoring as monitoring using blood tests. Renal function should be assessed Renal function should be assessed (calculate Renal function should be assessed (calculate (calculate CrCL):  in all patients before starting dabigatran  in all patients before starting rivaroxaban  in all patients before starting apixaban and
 at least once a year6  at least once a year6  at least once a year6 A number of cases of serious and fatal haemorrhage have been reported in elderly patients with renal impairment who were receiving dabigatran. Efficacy
A meta-analysis found for all Dabigatran 150 mg BD superior to warfarin Rivaroxaban 15 mg or 20 mg OD non- Apixaban 2.5 mg or 5.0 mg BD superior to for prevention of stroke and systemic inferior to warfarin for prevention of stroke warfarin for the prevention of stroke or Relative risk reduction: 64%, embolism; dabigatran 110 mg non-inferior and systemic embolism.3 systemic embolism.4 Absolute risk reduction: 2.7%. TTR of 65% or higher is Mean TTR in warfarin arm of pivotal trial: Mean TTR in warfarin arm of pivotal trial: 55% Mean TTR in warfarin arm of pivotal trial: 62%4 therapeutic range considered to represent good
(trial population with high risk for stroke)3 control of warfarin therapy.8 Average TTR in the UK is 63%.11 Long-term safety based on 50 No information available on long-term safety. No information available on long-term safety. No information available on long-term safety. years use in clinical practice. Contraindicated if CrCL <30 mL/min
Dose reduction recommended where CrCL Not recommended if CrCL <15 mL/min.
15-49 mL/min.
Not recommended if CrCL <15 mL/min.
This information is a summary to guide prescribers – for further information please consult individual SPCs at www.medicines.org.uk. RDTC 2014
Warfarin9
Dabigatran6
Apixaban7
Bleeding
See respective agent for Major bleeding: Major bleeding: Major bleeding: No difference between dabigatran 150 mg No difference between rivaroxaban and Less common with apixaban than warfarin BD and warfarin. Less common with dabigatran 110 mg BD than warfarin GI bleeding: GI bleeding: GI bleeding: More common with rivaroxaban than warfarin No difference between apixaban and warfarin More common with dabigatran 150 mg BD Intracranial bleeding: than warfarin (p=0.0008). No difference Intracranial bleeding: less common with between dabigatran 110 mg BD and Less common with apixaban than warfarin rivaroxaban than warfarin (p=0.02) Under additional monitoring via MHRA Black Intracranial bleeding: Triangle scheme as of February 2014. Less common with both doses of dabigatran than with warfarin (p<0.001). Bleeding risk high in the frail and elderly, particularly with renal impairment and low body weight. Side effects
Other side effects can include Dyspepsia more frequent with both doses of There were no significant differences in the There were no significant differences between dabigatran than warfarin. GI adverse events incidence of any adverse event other than warfarin and apixaban in the incidence of any frequently led to drug discontinuation (7%, bleeding in the pivotal rivaroxaban trial.3 adverse events in the pivotal apixaban trial.4 6.5% and 3.9% in the dabigatran 150 mg, The rate of MI was numerical y, but not 110 mg and warfarin groups respectively). statistically significantly, lower in the The rate of myocardial infarction (MI) was rivaroxaban arm compared with warfarin. numerically, but not statistically significantly, higher with dabigatran in the pivotal trial (0.82% for 110 mg and 0.81% for 150 mg vs. 0.64% p=0.12).2,12,13 A meta-analysis combining 7 studies showed dabigatran was associated with a significantly higher risk of MI or ACS. The control group varied and included enoxaparin, warfarin and placebo.14 Reversibility
Effective and well known No antidote currently known. Patients with No antidote currently known although No antidote currently known. antidote, should a severe bleed bleeding risk factors excluded from pivotal prothrombin complex concentrate has been occur whilst being treated successful in showing normalisation of Clearance can be increased with laboratory clotting parameters (prothrombin time and endogenous thrombin potential) in a small preliminary trial.16 Consequences of the lack of an effective reversal agent should not be underestimated. Prolonged bleeding has increased morbidity and possibly contributed to deaths.15 This information is a summary to guide prescribers – for further information please consult individual SPCs at www.medicines.org.uk. RDTC 2014
Warfarin9
Dabigatran6
Apixaban7
Switching
Switching to warfarin:1 Dosing Switching from warfarin
Switching from warfarin
Switching from warfarin
of warfarin and NOAC should SPC guidance: stop warfarin, start
SPC guidance: stop warfarin, start
SPC guidance: stop warfarin, start apixaban
overlap until INR is >2.0. This dabigatran when INR is <2.0. rivaroxaban when INR is ≤3.0. when INR is <2.0. may take 5-10 days. EHRA guidance:1 initiate NOAC once INR is EHRA guidance:1 initiate NOAC once INR is EHRA guidance:1 initiate NOAC once INR is
Since NOACs can contribute to <2.0. If INR is 2.0-2.5, start NOAC <2.0. If INR is 2.0-2.5, start NOAC <2.0. If INR is 2.0-2.5, start NOAC immediately elevated INR, testing should be immediately or (better) next day. If INR >2.5, immediately or (better) next day. If INR >2.5, or (better) next day. If INR >2.5, estimate when performed just before the next estimate when INR is likely to drop below estimate when INR is likely to drop below this INR is likely to drop below this threshold, and NOAC dose is due. Re-test 24h this threshold, and re-test at that time. threshold, and re-test at that time. re-test at that time. after the last dose of NOAC to ensure adequate anticoagulation. Interactions
Drug-food interactions
Drug-food interactions
Drug-food interactions
Drug-food interactions
Cranberry juice and alcohol There are no known food interactions. There are no known food interactions. There are no known food interactions. interact with warfarin. Some foods interact with warfarin (e.g. foods containing high amounts Drug-drug interactions
Drug-drug interactions
Drug-drug interactions
Contraindicated with the strong P-gp
Not recommended with concomitant
Not recommended with concomitant systemic
inhibitors ketoconazole, cyclosporine, systemic administration of strong inhibitors of administration of strong inhibitors of both itraconazole, tacrolimmus and dronedarone. both CYP3A4 and P-gp, such as CYP3A4 and P-gp, such as ketoconazole, Drug-drug interactions
Use with caution if co-administered with
ketoconazole, itraconazole, voriconazole, itraconazole, voriconazole, posaconazole or Many interactions requiring mild to moderate P-gp inhibitors such as posaconazole or HIV protease inhibitors. additional INR monitoring. amiodarone, quiidine, verapamil, & Strong inducers of both CYP3A4 and P-gp Strong inducers of both CYP3A4 and P-gp (such as rifampicin, phenytoin, (such as rifampicin, phenytoin, carbamazepine, Co-administration with P-gp inducers such carbamazepine, phenobarbital or St John's phenobarbital or St John's Wort) should be co- as rifampicin, St John's Wort, Wort) should be co-administered with administered with caution.
carbamazepine or phenytoin) should be caution.
Concomitant administration with any other anticoagulants contraindicated.
SSRIs and SNRIs increased the risk of Concomitant administration with any other bleeding in RE-LY in all treatment groups. anticoagulants contraindicated.
Consult the SPC for full details of interactions Concomitant administration with any other anticoagulants contraindicated.
Consult the SPC for full details of interactions. Consult the SPC for full details of interactions. This information is a summary to guide prescribers – for further information please consult individual SPCs at www.medicines.org.uk. RDTC 2014
Warfarin9
Dabigatran6
v roxaban5
Apixaban7
Contraindications
Known hypersensitivity to  Hypersensitivity to the active substance  Hypersensitivity to the active substance  Hypersensitivity to the active substance or warfarin or any excipients or any excipients. or any excipients.  Haemorrhagic stroke  Severe renal impairment (CrCL < 30  Active clinically significant bleeding.  Active clinically significant bleeding.  Clinically significant  Concomitant treatment with any other  Hepatic disease associated with  Active clinically significant bleeding. coagulopathy and clinical y relevant  Within 72 hours of major  Any lesion or condition considered a  Hepatic disease associated with surgery with risk of severe significant risk factor for bleeding. coagulopathy and clinical y relevant  Any lesion or condition considered a  Concomitant treatment with any other bleeding risk including cirrhotic patients significant risk factor for bleeding.  Within 48 hours postpartum with Child Pugh B and C  Concomitant treatment with any other Pregnancy (first and third  Hepatic impairment or liver disease Pregnancy and breast feeding. expected to have any impact on  Drugs where interactions may lead to a significantly  Concomitant treatment with systemic increased risk of bleeding ketoconazole, cyclosporine, itraconazole, tacrolimus, dronedarone.  Prosthetic heart valves When should it be Intolerance to warfarin including AVOID in patients with a history of poor
AVOID in patients with a history of poor
AVOID in patients with a history of poor
avoided?
allergy, rash, side effects likely medication adherence. medication adherence. medication adherence. to result in discontinuation of therapy (other than bleeding complications) e.g. severe Dabigatran is not stable in compliance aids
Rivaroxaban is not a suitable alternative to
Apixaban is not a suitable alternative to
alopecia (although such as blister packs. warfarin in patients with bleeding warfarin in patients with bleeding complications acenocoumarol may be a complications associated with warfarin associated with warfarin treatment, suitable alternative in these treatment, contraindications to warfarin contraindications to warfarin therapy due to a Dabigatran is not a suitable alternative to
therapy due to a high bleeding risk, alcohol high bleeding risk, alcohol abuse, drug warfarin in patients with bleeding abuse, drug overdose or trivial side effects overdose or trivial side effects related to complications associated with warfarin related to warfarin. Demonstrated unmanageable treatment, contraindications to warfarin warfarin control e.g. due to long therapy due to a high bleeding risk, alcohol term interacting drug therapy abuse, drug overdose or trivial side effects (INR persistently and related to warfarin. significantly above or below range that does not respond to dose titration) Demonstrated impossibility of monitoring arrangements This information is a summary to guide prescribers – for further information please consult individual SPCs at www.medicines.org.uk. RDTC 2014

References
1. Heidbuchel H et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace;15:625-51.
2. Connolly SJ et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139-51.
3. Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2010;365:883-91.
4. Granger CB et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
5. Bayer plc. Summary of product characteristics - Xarelto 20 mg film-coated tablets. Last updated 26/07/13.
6. Boehringer Ingelheim. Summary of product characteristics - Pradaxa 150 mg hard capsules. Last updated 22/10/13.
7. Bristol-Myers Squibb-Pfizer. Summary of product characteristics - Eliquis 5 mg film-coated tablets. Last updated 01/10/13.
8. National Clinical Guideline Centre. Atrial fibrillation: the management of atrial fibrillation. Clinical guideline draft for consultation. January 2014. Commissioned by NICE.
9. Amdipharm Mercury Company Limited. Summary of product characteristics - Marevan 5 mg tablets. Last updated 07/12/12.
10. Hart RG. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67.
11. Gallagher AM et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011;106:968-77.
12. Connolly SJ et al. Supplementary appendix to Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139-51.
13. Hohnloser SH. Myocardial ischaemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-term anticoagulation therapy) Trial. Circulation
2012;125:669-76.
14. Uchino K et al. Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials. Arch Intern Med 2012.
15. Harper P. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366:864-6.
16. Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9.
Acknowledgements to Jo Bateman, Cardiology Pharmacist Countess of Chester Hospital and Dave Thornton Principal Pharmacist Clinical Services University Hospital Aintree.
Adapted from original by the Regional Drug & Therapeutics Centre, October 2013.
Version number: 1.6
Last revised: March 2014
PRESCRIBING SUPPORT

Source: http://www.hartlepoolandstocktonccg.nhs.uk/wp-content/uploads/2013/11/RDTC-NOAC-comparison-final-version.pdf

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Developments in International Commercial Mediation: USA, UK, Asia, India and the European Union By Danny McFadden LLM, FCIArb This paper will look at some of the major developments in international commercial mediation to date but the author would ask the reader to bear in mind that the picture is constantly changing which reflects the adaptability and dynamism of mediation in the modern era.