Dr Alan Begg revisits the SIGN antithrombotics guideline and highlights new evidence on novel oral anticoagulant agents

The prescribing of antithrombotic drugs is now an important aspect of primary care and also the quality and outcomes framework (QOF).1 Treatments include antiplatelet agents, mainly for the prevention of a cardiovascular event in patients with confirmed atherosclerotic disease, and anticoagulants for the prevention of an embolic event in patients with atrial fibrillation (AF). Despite the relevance of the topic, at the time of its publication in August 2012, the Scottish Intercollegiate Guidelines Network (SIGN) guideline 129 (SIGN 129) on Antithrombotics: indications and management 2 made little impact on clinicians and was not promoted in general practice. The guideline, which replaced SIGN 36 published in 1993,3 now includes a completely revised section on the prophylaxis of systemic embolism in AF, as well as a new chapter on newer antithrombotic drugs. SIGN 129 complements, and should be read alongside, a range of other SIGN guidelines, as listed in the guideline introduction.2

Antiplatelet drugs

The recommendation in SIGN 129 remains that the lowest dose of aspirin (75 mg) should be used in the prevention of vascular disease to minimise the risk of bleeding. Aspirin should not however be used in the primary prevention of vascular disease, on the basis that its benefits do not outweigh the risk of harm from an increased risk of haemorrhage. The guideline suggests that discontinuation of aspirin and dipyridamole is not generally required prior to an invasive procedure, although clopidogrel may need to be temporarily discontinued 7 days prior to such a procedure. If a coronary stent has been inserted in the previous 12 months, then clopidogrel should only be stopped on the advice of a cardiologist.2

In those patients taking an antiplatelet agent who are at high risk of gastrointestinal bleeding, the concomitant use of a protein pump inhibitor (PPI) is beneficial, more so than with an H2-receptor antagonist (H2RA), in reducing the risk of haemorrhage.2 These drugs are also used for patients who find difficulty tolerating aspirin, mainly because of non-ulcer dyspepsia, to avoid the switch from aspirin to the more expensive clopidogrel, which is often better tolerated.4 As clopidogrel is now off patent and much cheaper, healthcare professionals are no longer under pressure to avoid prescribing this therapy. However, it has been suggested that, based on pharmacodynamic data, clopidogrel is less effective in preventing vascular events if given concomitantly with certain PPIs, although SIGN 129 indicates that the clinical effect remains unclear, and the risk of a thrombotic episode should be considered in each individual case when using these agents together.2

SIGN 129 is in agreement with NICE guidance that there is no advantage in the use of clopidogrel over aspirin for peripheral arterial disease;2,5 and also with the Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) trial that no advantage is seen for clopidogrel monotherapy in people with an ischaemic stroke, over the combination of aspirin and dipyridamole (hazard ratio, 1.01; 95% confidence interval [CI] 0.92 to 1.11).6 However, on the basis of NICE Technology Appraisal 210,7 a National Therapeutic Indicator in Scotland for 2012 is to incentivise GPs to move patients receiving the combination of aspirin and modified-release dipyridamole onto clopidogrel monotherapy.7,8 This is on the basis that generic clopidogrel is now the preferred cost-effective treatment for secondary prevention after an ischaemic stroke.

Oral anticoagulation

Within the UK, warfarin is the vitamin K antagonist that should be used for oral anticoagulation (see section 5 of SIGN 129); and heparin is not generally required when commencing prophylactic therapy for thromboembolism. Before therapy is commenced, baseline bloods, including a coagulation screen, should be performed and the patient should be advised to take daily drug doses at a fixed time. Warfarin does not need to be discontinued in patients undergoing dental surgery, including extractions. Interestingly, the guideline development group was unable to identify any evidence on the effects of exercise, stress, or lifestyle on the action of warfarin. The SIGN guideline does, however, list the potential difficulties for patients using warfarin, including the need for regular international normalised ratio monitoring, the effect of other drugs and diet on control of anticoagulation, the potential problems related to alcohol intake, and possible abnormal bleeding.2

Novel oral anticoagulant agents

An overview of the three novel oral anticoagulants (NOACs) currently available (rivaroxaban, dabigatran, and apixaban) is covered in a separate part (section 6) of SIGN 129,2 but as their use, especially in the prophylaxis of systemic embolism, has developed rapidly, the guideline is no longer up to date in relation to this class of drugs. When SIGN 129 was published in 2012, the evidence for apixaban had been published, but the drug was only accepted for use within NHS Scotland by the Scottish Medicines Consortium (SMC) in January 2013, for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation.9,10 NICE issued its technology appraisal on Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation in February 2013. 11

As with SIGN 93 on Acute coronary syndromes, which has been updated twice since publication, 12 there is a need to consider an update to SIGN 129 to take into account changing evidence and practice and to bring the recommendations into line with the focused update to the European Society of Cardiology (ESC) guideline on AF.13

Systemic embolism prophylaxis in atrial fibrillation

The SIGN guideline reminds us that an echocardiogram, to determine whether or not there is valvular disease or impairment of left ventricular systolic dysfunction, is considered an optimal part of the assessment of a patient with AF.2 The echocardiogram is often essential in determining the most effective treatment, especially where GPs are treating patients who have permanent AF without referral to secondary care. Instances of where this service is not being uniformly provided need to be addressed and taken into account by clinical commissioning groups.

The guideline recommends performing a risk assessment using CHADS2 or CHA2DS2-VASc in patients with AF,2 but in line with the ESC guideline13 the implication is that CHA2DS2-VASc is preferred. In people aged less than 65 years with lone AF and a CHA2DS2-VASc score of 0 in males, and 1 in females, where 1 is allocated for the female sex, then no antithrombotic therapy is required. In all other individuals, anticoagulation with warfarin or a NOAC is required; antiplatelet therapy has no role in treatment unless warfarin or a NOAC has been declined. Drawbacks of the NOACs include:2

  • the relative lack of experience of long-term use compared with warfarin
  • the lack of a rapid reversal agent
  • potentially higher rates of gastrointestinal bleeding
  • limited data on use in people at extremes of body weight, and those with renal impairment.

After an acute stroke with associated AF, anticoagulation should be commenced after 2 weeks in the absence of haemorrhage, although this should be delayed in the presence of a large infarct because of the risk of haemorrhagic transformation.2

Conclusion

The introduction of NOACs has led to a significant change in how GPs manage patients with AF, and has resulted in out-of-date recommendations on these agents in SIGN 129; an update to correct this deficiency is required. An awareness of indirect clinical and cost-effectiveness comparisons of NOACs14 will help ensure that formulary and prescribing decisions do not adversely affect direct patient care.

  • Although SIGN guidance relates to Scotland, many of the issues also relate to clinical commissioning in England
  • The recommendation from the European Society of Cardiology on the use of CHA2DS2-VASc over CHADS2 in non-valvular atrial fibrillation is yet to be reflected in the quality and outcomes framework, or indeed recommended for use by NICE
  • CCGs may wish to consider local incentive schemes to encourage practices to follow CHA2DS2-VASc if they consider the evidence on reducing thrombotic events in atrial fibrillation to be robust, and pending further guidance from SIGN or NICE
  • The place of NOACs in the prophylaxis of thrombotic events in non-valvular atrial fibrillation should be clarified by CCGs in local formularies as NICE does recommend them as an option to consider against warfarin within their licensed indications
  • NOACS are considerably more expensive than warfarin, but do not require regular blood monitoring so CCGs could identify the circumstances where they may be advantageous over warfarin in their formularies (e.g. in poor control of international normalised ratio using warfarin, or difficulty performing regular blood tests in itinerant, or housebound, individuals)
  • CCG formularies should be adapted to clearly define the local choices and licensed indications for antithrombotic agents in secondary prevention of coronary heart disease, peripheral arterial disease, transient ischaemic attack, and stroke.

CCG=clinical commissioning group; NOAC=novel oral anticoagulant

  1. British Medical Association, NHS Employers, NHS Commissioning Board. Quality and outcomes framework guidance for GMS contract 2013/14. London: BMA, NHS Employers, NHSCB, 2013. Available at: bma.org.uk/practical-support-at-work/contracts/independent-contractors/qof-guidance
  2. Scottish Intercollegiate Guidelines Network. Antithrombotics: indications and management. SIGN 129. Edinburgh: SIGN, 2012. Available at: www.sign.ac.uk/pdf/SIGN129.pdf nhs_accreditation
  3. Scottish Intercollegiate Guidelines Network. Antithrombotic therapy. SIGN 36. Edinburgh: SIGN, 1999.
  4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348 (9038): 1329–1339.
  5. NICE. Lower limb peripheral arterial disease: diagnosis and management. Clinical Guideline 147. London: NICE, 2012. Available at: www.nice.org.uk/guidance/CG147 nhs_accreditation
  6. Diener H, Sacco R, Yusuf S et al. Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008; 7 (10): 875–884.
  7. NICE. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of technology appraisal guidance 90). Technology Appraisal 210. London: NICE, 2010. Available at: www.nice.org.uk/ta210 nhs_accreditation
  8. Hurding S, MacBride-Stewart S. National therapeutic indicators 2012—baseline data. Quality and Efficiency Support Team—Scottish Government Health and Social Care Directorate. Available at: www.sehd.scot.nhs.uk/pca/PCA2012(M)08report.pdf
  9. Scottish Medicines Consortium. Apixaban 2.5 mg and 5 mg film coated (Eliquis). SMC No (836/13). SMC, 2013. Available at: www.scottishmedicines.org.uk/SMC_Advice/Advice/836_13_apixiban_Eliquis/apixaban_Eliquis
  10. Granger C, Alexander J, McMurray J et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11): 981–992.
  11. NICE. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. Technology Appraisal 275. London: NICE, 2013. Available at: www.nice.org.uk/guidance/TA275 nhs_accreditation
  12. Scottish Intercollegiate Guidelines Network. Acute coronary syndromes. SIGN 93. Edinburgh: SIGN, 2007, updated 2013. Available at: www.sign.ac.uk/guidelines/fulltext/93/index.html
  13. Camm A, Lip G, De Caterina R et al. Focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33 (21): 2719–2747.
  14. Dentali F, Riva N, Crowther M et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126 (20): 2381–2391. G