This series discusses two new antiplatelet and four new oral anticoagulant (OAC) medications which GPs are increasingly finding on routine repeat prescriptions. This second part focuses on the new oral anticoagulants on the market


Dr Jane Wilcock GP, Silverdale Medical Practice, Salford CCG, co-year 3-4 Director and Tutor University of Liverpool School of Medicine 


For the first part in the series, click here


In the last edition of the British Journal of Family Medicine we looked at the use of the two most commonly prescribed antiplatelet drugs, aspirin and clopidogrel, and how new antiplatelets to market – prasugrel (Efient) and ticagrelor (Brillique) – are changing treatment and prescribing.

This article will focus on the four new oral anticoagulants that are on the market and GPs will be seeing more regularly on repeat prescription forms – dabigatran, rivaroxaban, apixaban and edoxaban.

New oral anticoagulant drugs in general practice

OACs are used primarily in prevention of thrombus in AF and VTE (DVT and PE). They are also also used in antiphospholipid syndrome, genetic thrombotic disorders, cardiomyopathy, rheumatic heart disease and after prosthetic heart valve implant.

The National Stroke Audit1 revealed that the mean age of stroke is 77 years old and that 20% of patients with non-haemorrhagic stroke (iCVA) are admitted in AF. NICE recommends that patients with non-valvular AF and at risk of stroke are treated with OACs, but in the National Stroke Audit 34% of patients in AF were taking an antiplatelet, only 44% were on an oral anticoagulant and 4% were on both an antiplatelet and an oral anticoagulant when admitted with CVA. It is estimated that 2.4% of adults in England are taking anticoagulants per annum2 and this figure is likely to rise. OAC should be offered to people with a CHA2DS2VASc score of 2 or more, and considered for men with a CHA2DS2VASc score of 1, taking bleeding risk using HAS-BLED into account.3 AF ischaemic stroke risk assessment can be estimated by free online tools using CHA2DS2Vasc scoring and statistical bleeding risk using the HAS-BLED scoring system.4

Warfarin is a vitamin K antagonist (VKA) and prevents formation of active clotting factors F2, F7, F9, F10 and proteins C, S and Z.5 The novel oral anticoagulants (NOACs) have more specific actions. Dabigatran is a thrombin (F2) inhibitor and the others, rivaroxaban, apixaban and edoxaban, are F10 inhibitors. Warfarin has been in use since the 1950s and is the most commonly prescribed OAC.6 It is not ideal as it has a narrow therapeutic range and non-uniform dosing, meaning it is difficult to place in elderly patients’ monitored dosage systems (MDS), like venalinks (where medications are delivered weekly to the patients and set up in divided daily blister packs) to improve compliance among elderly forgetful individuals. 

Patients and their carers need to be familiar with the different tablets; blue (3mg) and brown (1mg) tablets. They also need to understand their daily dosage schedule. It is difficult to predict warfarin metabolism due to genetic variability and patients must attend for monitoring of INR, with its cost implications, or have training to undertake monitoring themselves. Patients are frequently under or over coagulated, referred to as “time in therapeutic range” or TTR. In a recent study, mean TTR was 56%.7 Over 70% TTR is considered gold standard, but this still leaves 30% of the patient’s time in an either under or over anti-coagulated state. Warfarin requires patients to have a consistent diet without times of fasting and to avoid excessive or non-uniform alcohol use. There are numerous interactions with other liver metabolised medications as it is metabolised through the p450 cytochrome complex. There is the added cost of INR monitoring in psychosocial terms. Having a long half-life has a small upside in that missing a dose does not return coagulation immediately to normal.

The NOACs have gained a place in therapy as they are a uniform daily dosing and do not require monitoring, so freeing patients up to manage their own time and reduce the medicalisation of their illness. Some are once a day, which further improves compliance. There are reduced doses for those at high risk of bleeding, the elderly, lightweight individuals and those with reduced eGFRs. They have been shown to be as effective as warfarin in action. The last of these, edoxaban, has little data as it has only just been approved for UK use. NOACs have fewer drug interactions than warfarin and work more quickly with shorter half lives. Advice about missing doses or taking too many tablets can be found in the European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation produced in 2013, and it would be useful to keep this reference on the GP desktop. In missed NOAC once daily dosing the missed tablet can be taken up to 12 hours after scheduled intake or otherwise skipped. In patients on a twice daily NOAC the patient can take the forgotten dose up to six hours after the intended medication time. If the patient has taken a double dose and is on a once a day tablet they should continue their usual regime. On a twice a day dose they could miss the second dose. Overdose requires hospital assessment.

The specialist or GP initiating therapy must counsel the patients, consider risk factors, ensure baseline FBC, eGFR and LFTS are normal and check other medications, including over-the-counter preparations, for interactions. The doctor should consider the need for proton pump inhibitor (PPI) co-prescription if there is a concern about risk of peptic ulceration.

Antidotes to NOACs are in development. Patients do not have a monitoring booklet, as INR is not required, but have a manufacturer’s alert card which they should carry on their person. NOACs are excreted through the kidneys and so dosage and use may vary with eGFR. Dabigatran is not used in an eGFR<30mls/min and the others below15mls/min. Annual eGFR is suggested as a minimum, more often in CKD but also in inter-current illness when acute kidney injury might occur.8

It is important for GPs to use the BNF to check for interactions and indications. NICE and the European Heart Rhythm Association recommend seeing patients every three months on NOACs to check on thrombotic problems, bleeding problems, polypharmacy, interactions, compliance and patient education. As experience of these medications improves hopefully confidence in patient tolerability will ensue. Anticoagulant assays and INRs are not required. If the patient appears to be under or over-anticoagulated on a NOAC the GP should ask for expert assessment and tests. A six-month study of dabigatran and rivaroxaban did not show any deterioration in renal or liver function. Both drugs affect PTT, and so INR, and APPT but at a specialist non-linear level so the use of INR or APPT is not recommended in monitoring therapy.9

Dabigatran

This is a pro-drug with a dose of 150, or 110mg or 75mg a day. It has a half life of 13 hours and works within one-three hours. It is secreted through the kidneys so elimination relates to renal function.10 The MHRA recommend checking renal function at the start of therapy and then annually, avoiding use if eGFR<30mls/min. The dose used reduces with eGFR (see BNF). It should be used with caution in patients with a weight <50kg and in the elderly. Elderly is defined as >75 and >80 years old, according to differing indications and again affects dosing. In addition, dabigatran should be avoided, or the dose reduced, with some medications. Careful use of the BNF in prescribing NOACs is required. The BNF has an excellent section under interactions for each of the NOACs. It is known to interact with amiodarone, verapamil, carbamazepine, dronedarone, SSRIs increase bleeding risk, clarithromycin, itraconazole, ketoconazole, NSAIDs, St John’s Wort, antifungals and tacrolimus. It is the only NOAC not suitable for patient compliance aids, MDS, as it hydrolyses when out of its packaging and so capsules also should not be opened. It is contraindicated in patients with mechanical heart valves because, when compared to warfarin for patients who had had mechanical heart valve replacement, it increases the patient’s bleeding risk.10 Dyspepsia can be a side-effect.11

Indications are prevention of VTE post knee (nine days therapy) or hip replacement (27-34 days of therapy), treatment (following five days of LMW heparin) of VTE or secondary prevention of VTE and stroke and other embolism prevention in patients at risk with non-valvular AF.

Rivaroxaban

This is the most commonly prescribed NOAC and is a F10a inhibitor. It has tablet doses of 2.5, 10, 15 and 20mg and once or twice a day dosing depending on indication. It is effective within four hours and has a half life of 5–13 hours.5 It has the same indications as dabigatran, so used after knee or hip replacement to prevent VTE, treatment of VTE and prevention of systemic embolism, and iCVA in non-valvular AF if anticoagulation is considered beneficial after risk scoring. In addition, rivaroxaban is also indicated for patients after MI with aspirin, or with aspirin and clopidogrel at a low dose of 2.5mg bd usually for 12 months.12 This significantly reduces the rate of death from CHD and CVA without increasing fatal bleeding, but there is an increased risk of major haemorrhage amongst patients.13 The dose is reduced in patients with reduced eGFR and it is not used in eGFR<15mls/min. It is the only NOAC with advice regarding food – it should be taken with food, which increases its bioavailability.3 It is suitable for use in an MDS. As it is metabolised through the CYP liver complex it interacts with carbamazepine, dronedarone, itraconazole, ketoconazole, antiviral drugs and others, also with St John’s Wort but there is no interaction with atorvastatin.8 The commonest side-effect is nausea.

Apixaban

This drug is indicated for prevention of VTE post hip and knee replacement, for treatment of VTE, and prevention of systemic embolisation and iCVA in non valvular AF, just like the other NOACs. The Aristotle trial suggested apixaban was superior to warfarin in both reduction of iCVA or systemic embolism and major bleeding in patients with non valvular AF. In the elderly age group ( =80 years old), stroke or systemic embolism was reduced from 1.9% per year with warfarin to 1.53% per year with apixaban, major bleeding from 5.41% per year with warfarin to 3.55% per year with apixaban and ICH from 1.32% per year with warfarin to 0.47% per year with apixaban, which were all statistically significant.14

It is dosed at 5mg or 2.5mg bd and is effective in two hours with a half life of 8-15 hours. It is liver CYP metabolised and so interacts with antiviral drugs, antifungals, clarithromycin and St John’s Wort. It is suitable for use in MDS. The dose is reduced with declining eGFR and avoided in eGFR<15mls/min. In non-valvular AF the dose is reduced if the patient is >80 years old.

Edoxaban

This is a new F10a inhibitor and is dosed at 60mg or 30mg once daily. It is effective in one–two hours and has a half life of five-11 hours. It is CYP metabolised and has just received authorisation from NICE for the prevention of recurrent deep vein thrombosis and pulmonary embolism in adults. NICE has approved edoxaban for use in non-valvular AF with risk factors in Sept 2015. It’s side-effect profile includes care in hepatobiliary disorders.

Conclusions

In my practice there are 11,900 patients and we have 18 patients on ticagrelor, one on prasugrel, four on dabigatran, 24 on rivaroxaban and six on apixaban. GPs should keep up to date with these medications and the local arrangements for continuing, considering or commencing NOAC and antiplatelet use via their medicines management support units. Due to the variability in prescription length for STEMI and NSTEMI, GPs require a system to highlight repeat prescriptions and when the drug should be reviewed and is expected to be stopped. Patients with difficult PCI procedures, multiple indications or continuing thrombotic problems, despite antiplatelets or OACs, will often find themselves on crossover and combined therapies of antiplatelets and OACs in order to prevent further thrombosis.

Patient safety issues are paramount, as patients with CHD and multiple morbidities, like COPD, will usually be on other liver metabolising medications and may also have chronic kidney disease (CKD) due to atheroma in the aorta or renal arteries or suffer from concomitant diabetes. These medications appear to offer improvements on older therapies and the use of NOACs compared to warfarin should, in the long-term, save patients and the NHS time, but, in the short term, require longer consultation and administrative times for GPs to ensure safe and effective prescribing.


References:

1. Sentinel Stroke National Audit Programme (SSNAP) Clinical audit January—March 2015 public report National results July 2015 Royal College of Physicians https://www.strokeaudit.org/Documents/Results/National/JanMar2015/JanMar2015-PublicReport.aspx
2. Support for commissioning: anticoagulation therapy. NICE commissioning guides [CMG49] Published date: May 2013
3. Supporting local implementation of NICE guidance on use of the non-Vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation Consensus statement 2014 https://www.nice.org.uk/guidance/cg180/resources/cg180-atrial-fibrillation-nic-consensus-statement-on-the-use-ofnoacs2 
4. Web addresses for AF risk scoring. http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/http://www.mdcalc.com/has-bled-score-for-major-bleedingrisk/
5. Pirohamed M., Kamali F., Daly A.K. and Wadelius M. Trends in Pharmacological Science March 2015.36(3); pp. 153-163
6. Prescription Cost Analysis, England – 2014 [NS] April 08, 2015. Health and Social Care Centre. http://www.hscic.gov.uk/catalogue/PUB17274/pres-costanaleng-2014-rep.pdf
7. Asarcikli L.D., Sen T., Ipek E.G. et al. J Am Coll Cardiol. 2013; 62 (18-S2):pp.127-128.
8. Heibuchel H., Verhamme P., Alings M., et al, European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation April 2013 http://europace.oxfordjournals.org/content/15/5/625
9. Gorzelak- Pabis P, Duraj I., Szlagowska L et al, Pol Merkur Lekarski 2014. 37;221:pp261-264
10. Dabigatran (Praxada): contraindicated in patient with prosthetic heart valve(s) requiring anticoagulant treatment Drug Safety Update MHRA http://www.gov.uk/drug-saftey-update/dabigatran
11. BNF https://www.medicinescomplete.com/mc/bnf/current/PHP1503-dabigatran-etexilate.htm
12. BNF https://www.medicinescomplete.com/mc/bnf/current/PHP1511-rivaroxaban.htm
13. Cheng JVV., Barillari G. J Clin Pharm. Ther. 2014. 39 (2):pp.118-35
14. Halvorsen S., Atar D., Yang H., et al, N Engl J Med 2011. 365; pp.981-992.