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Consider aspirin for primary prevention of cardiovascular events if risk is high

Select patients for aspirin by assessing their overall cardiovascular risk and risk of bleeding

Aspirin (100–300 mg daily) may be used to prevent a first coronary heart disease or stroke event due to arterial disease (atherothromboembolism) when the overall absolute risk is > 15% over 5 years.[1,2]

Use an absolute risk assessment tool to identify patients at high cardiovascular risk.[A] To guide treatment decisions, assess risk factors for bleeding with aspirin including increasing age, any bleeding predisposition, history of peptic ulcer, uncontrolled hypertension, severe renal or hepatic impairment, and concurrent use of NSAIDs or anticoagulants.[3,4]

[A] Use the National Vascular Disease Prevention Alliance (NVDPA) paper-based tool or online calculator, or until these are available, the New Zealand Guidelines Group Cardiovascular Risk Calculator.

Aspirin, aspirin plus dipyridamole, or clopidogrel are the main antiplatelet options for secondary prevention of stroke due to arterial disease

Use long-term antiplatelet therapy after an ischaemic stroke or transient ischaemic attack (TIA) due to arterial disease

Antiplatelet therapy reduces the relative risk of stroke, myocardial infarction or vascular death by 22% (95% confidence interval [CI] 14% to 30%) in people with an ischaemic stroke or TIA due to arterial disease, compared with no treatment.[5]

Aspirin should be given as soon as possible after the onset of ischaemic stroke and can be continued as long-term antiplatelet therapy.[2] Clopidogrel (Iscover, Plavix) or aspirin plus dipyridamole sustained release (Asasantin SR) are other options for initial long-term therapy, or if stroke re-occurs while taking aspirin.[2]

Reserve dipyridamole alone or ticlopidine for when neither aspirin nor clopidogrel is tolerated.[2] Severe adverse effects with ticlopidine limit its use: skin rash, diarrhoea and neutropenia are more common than with clopidogrel or aspirin.[6]

Aspirin plus dipyridamole SR reduces stroke risk over aspirin alone, but is less well tolerated

In people with a previous stroke or TIA aspirin plus dipyridamole reduces the relative risk of non-fatal stroke by 23% (95% CI 11% to 33%) compared with aspirin alone, without causing excess bleeding.[7-9] However, this combination is often not tolerated: in the ESPRIT trial, more patients stopped aspirin plus dipyridamole than they did aspirin (34% vs 13%), mainly because of headache.[9]

Headache may improve by substituting low-dose aspirin for the morning dose of aspirin plus dipyridamole SR for a short period (e.g. < 1 week).[10] Avoid immediate-release dipyridamole; this has limited evidence of efficacy in stroke.[7]

Compared with aspirin alone, adding dipyridamole to aspirin has not been found to:

• prevent more vascular deaths
• provide additional benefit in coronary heart disease.[8]

Clopidogrel may be a more suitable choice for some patients

Clopidogrel alone has similar efficacy to aspirin plus dipyridamole SR in preventing recurrent stroke, and a comparable risk of major bleeding.[11] Clopidogrel may be a useful alternative for patients who:

• do not tolerate aspirin plus dipyridamole SR, or
• have co-existing coronary heart disease.[8,12]

Low-dose aspirin is also an effective option in these scenarios and is more affordable for people who do not meet the PBS authority restrictions for clopidogrel.[B] In the CAPRIE trial, the rate of serious vascular events in people with ischaemic stroke, myocardial infarction or peripheral arterial disease was slightly lower with clopidogrel than aspirin (5.3% vs 5.8%), but the overall risk of bleeding was similar (9.3% each).[13]

[B] Hypersensitivity to aspirin or NSAIDS (anaphylaxis, urticaria or asthma), unacceptable risk of gastrointestinal bleeding, recurrent vascular episodes while taking aspirin and use in combination with aspirin for acute coronary syndromes (myocardial infarction and unstable angina).

Avoid aspirin with clopidogrel, unless acute coronary heart disease is present

In the MATCH trial, aspirin with clopidogrel was no more effective than clopidogrel alone in preventing vascular events after ischaemic stroke or TIA (16% vs 17%), but caused more life-threatening bleeding (3% vs. 1%).[14]

The benefit of using aspirin with clopidogrel exceeds the risk of bleeding in patients with an acute coronary syndrome or coronary stent.[1,12]

Warfarin is the antithrombotic drug of choice for most people with atrial fibrillation

Consider long-term warfarin for every patient with AF at moderate to high risk of thromboembolic stroke

People with atrial fibrillation (AF) should receive warfarin if they are at moderate or high risk of stroke (Box 1), provided the benefits exceed their bleeding risk.[2,15-17] Valvular AF poses a particularly high risk of thromboembolism that needs anticoagulant therapy for stroke prevention.[15,18]

Warfarin reduces the relative risk of stroke in people with non-valvular AF by 64% (95% CI 49% to 74%) compared with placebo or no treatment.[19] Treating 12 patients for 1 year can prevent one recurrent stroke.[19] Treating 37 patients for 1 year can prevent one stroke as a first event.[19]

Box 1: Risk of thromboembolic stroke in atrial fibrillation[15,17]

Aspirin is less effective than warfarin in AF, but is an alternative for some patients

In people with non-valvular AF, aspirin reduces the relative risk of stroke by 22% (95% CI 2% to 39%) compared with placebo.[19] Warfarin is more effective but doubles the risk of major bleeding compared with aspirin: trials have found the absolute increase in risk to be small (0.2% per year), but this may be higher in practice for some patients.[19,20]

Aspirin is recommended for people at low risk of thromboembolism, as warfarin is more likely to cause a major bleed than prevent a stroke in these patients.[16] Aspirin is also an alternative for those at moderate risk of thromboembolic stroke or with contraindications to warfarin.[1,12,15]

Using aspirin with clopidogrel is not safer or more effective than warfarin in AF

The annual rate of serious vascular events in a trial was higher for aspirin with clopidogrel (5.6%) than for warfarin (3.9%), while the rate of major bleeding was similar (2% per year).[21]

Some patients who take warfarin may be prescribed aspirin, with or without clopidogrel, to reduce their risk of recurrent coronary heart disease events.[1,4,16]

Assess the balance of benefits and harms of warfarin to guide choice of antithrombotic therapy in non-valvular AF

Stratify stroke risk in non-valvular AF using the CHADS₂ index

The CHADS₂ index is a validated stroke risk stratification tool that assists with selecting patients with non-valvular AF for warfarin or aspirin (Table 1).[21]

The sum of points from the CHADS₂ criteria gives a risk score. For example:

Table 1: CHADS₂ stroke risk stratification in non-valvular atrial fibrillation[17,20,21]

Assess bleeding risk subjectively and reassess regularly

There is limited evidence for informing decisions about warfarin or aspirin based on bleeding risk, particularly for people at moderate risk of thromboembolic stroke.[18,23] Choice of therapy is thus guided by a subjective assessment of the benefit–harm profile for an individual.[18]

Avoid warfarin in people with: bleeding disorders; previous gastrointestinal, intracerebral or retinal haemorrhage; bacterial endocarditis; uncontrolled hypertension; heavy alcohol intake; significant liver disease; unsupervised dementia; or potential lack of adherence with monitoring.[4,16]

Major risk factors for bleeding may not contraindicate warfarin

People at high risk of bleeding are often also at high risk of thromboembolic stroke, but warfarin may still be indicated in these people if they are likely to gain more benefit than harm from therapy.[14,16,23] Older age (especially ≥ 75 years), propensity for falls and previous stroke are major risk factors for bleeding, but are not absolute contraindications to warfarin.[16]

Consider patient preference and other factors to guide choice of therapy

Explain to patients the relative benefits and harms of using warfarin or aspirin. Consider their preference, access to anticoagulation monitoring and other important factors (e.g. potential drug interactions) in treatment decisions.[14,17,21]

Maintain INR in therapeutic range to reduce stroke and bleeding risk

Avoid high loading doses of warfarin and frequent or large dosage adjustments

Start warfarin at 5 mg daily for 2 days then adjust the dose to an INR of 2–3 (higher for patients with prosthetic heart valves).[2,4,24] Elderly people may require lower doses.[4,24] Do not target a lower INR range (e.g. 1.5–2.0): this does not reduce the risk of bleeding and is less effective at preventing stroke than adjusting the dose of warfarin to achieve an INR of 2–3.[18,23,24]

Be aware of interactions with commonly used medicines and foods

The risk of bleeding with warfarin may be increased by amiodarone, antibiotics (particularly macrolides [e.g. erythromycin], metronidazole and quinolones [e.g. ciprofloxacin]), azole antifungals, paracetamol (> 3.5 g/week), selective serotonin re-uptake inhibitors (SSRIs) or large quantities of cranberry juice.[4] Some drugs increase bleeding risk with warfarin without changing the INR (e.g. aspirin, NSAIDs).[4] Refer to the Australian Medicines Handbook for information on interactions with warfarin.

Organise warfarin education for every patient

All patients starting warfarin should receive verbal counselling and an anticoagulant booklet. Pharmacists can undertake warfarin education during a Home Medicines Review, hospital admission or in a community pharmacy.

Use strategies that assist concordance with antithrombotic therapy

Discuss cardiovascular risk to help patients understand the need for antithrombotic therapy

Perceptions of risk differ between patients, and how risk is communicated can influence the decisions they make about treatments.[27,28] Provide individualised information on absolute cardiovascular risk (using numbers and words) and present the positive and negative scenarios of therapeutic choices.[27]

Use patient decision aids to guide treatment decisions

Using patient decision aids with health practitioner counselling improves levels of knowledge and realistic expectations about treatment options.[29] An audio booklet decision aid has been developed for patients with AF by the Canadian Stroke Network. It includes visual aids describing the benefits and harms of warfarin and aspirin.[30,31]

Reviewer

Prof Graeme Hankey,
Head of Stroke Unit, Royal Perth Hospital
Clinical Professor, School of Medicine and Pharmacology,
University of Western Australia

References

1. Cardiovascular Expert Group. Therapeutic Guidelines: Cardiovascular, Version 5. In: eTG complete [CD-ROM]. Melbourne: Therapeutic Guidelines Limited; July 2008.
2. Neurology Expert Group. Therapeutic Guidelines: Neurology, Version 3.  In: eTG complete [CD-ROM]. Melbourne: Therapeutic Guidelines Limited; July 2008.
3. Hankey GJ, Eikelboom JW. Med J Aust 2003;178:568–74.
4. Australian Medicines Handbook, 2008.
5. Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86.
6. Hankey GJ, et al. Cochrane Database Syst Rev 2000;(1):CD001246.
7. Verro P, et al. Stroke 2008;39:1358–63.
8. De Schryver E, et al. Cochrane Database Syst Rev 2007;(3):CD001820. 
9. Halkes PHA, et al. Lancet 2006;367:1665–73.
10. Boehringer Ingelheim Pty Ltd. Asasantin SR Product Information; 31 July 2008.
11. Sacco R, et al. N Engl J Med 2008;359:1238–51.
12. National Stroke Foundation. Clinical Guidelines for Stroke and TIA Management. A guide for general practice, 2008.  (accessed 8 September 2008).
13. CAPRIE Steering Committee. Lancet 1996;348:1329–39.
14. Fuster V, et al. Eur Heart J 2006;27:1979–2030.
15. New Zealand Guidelines Group (NZGG). The management of people with atrial fibrillation and flutter. Evidence-based best practice guideline; May 2005. (accessed 9 September 2008).
16. Singer DE, et al. Chest 2008;133:546S–92S.
17. Medi C, et al. Med J Aust 2007;186:197–202.
18. Hart RG, et al. Ann Intern Med 2007;146:857–67.
19. Hylek EM, et al. Circulation 2007;115:2689–96.
20. Gage BF, et al. JAMA 2001;285:2864–70.
21. Strong SH, Halperin JL. Geriatrics 2007;62:22–7.
22. Baker RI, et al. Med J Aust 2004;181:492–7.
23. Perret-Guillaume C, Wahl DG. Thromb Haemost 2004;91:394–402.
24. Hylek EM, et al. N Engl J Med 2003;349:1019–26.
25. Diener H-C, et al. Lancet 2004;364:331–7.
26. Connolly S, et al. Lancet 2006;367:1903–12.
27. Healey JS, et al. Stroke 2008;39:1482–6.
28. Paling J. BMJ 2003;327:745–8.
29. Moore RA, et al. Arthritis Res Ther 2008;10 (doi:10.1186/ar2373):R20.
30. O'Connor AM, et al. Cochrane Database Syst Rev 2003;(1):CD001431.
31. Man-Son-Hing M, et al. JAMA Vol 1999;282:737–43.
32. McAlister FA, et al. CMAJ 2005;173:496–501.