Using antithrombotics: maximising benefits; minimising risks (Prescribing Practice Review)

Published in MedicineWise News

Date published: About this date

Clinical content may change after this date. This information is not intended as a substitute for medical advice from a qualified health professional. Health professionals should rely on their own expertise and enquiries when providing medical advice or treatment.

Key messages

  • Consider warfarin in all patients with atrial fibrillation at moderate-to-high risk of thromboembolism
  • Regularly monitor INR and review risk factors for bleeding—these are key to enhancing safe warfarin use 
  • Low-dose aspirin remains the drug of first choice over other antiplatelet agents for cardiovascular prophylaxis
  • Where the absolute risk of coronary heart disease events is low, the benefit of low-dose aspirin is no greater than the risk of bleeding

Antiplatelet drugs to prevent cardiovascular events

Note: In this article ‘antiplatelet drugs’ refers to aspirin, dipyridamole (Persantin, Asasantin SR), clopidogrel (Iscover, Plavix) and ticlopidine (Ticlid, Tilodene).

Individuals at highest absolute risk of a coronary heart disease (CHD) event gain the greatest benefit from antiplatelet therapy

An updated systematic review1 included randomised controlled trials of antiplatelet therapy in patients at high risk of occlusive vascular disease (i.e. patients with acute or previous myocardial infarction, ischaemic stroke or transient ischaemic attack (TIA), stable and unstable angina, peripheral arterial disease, or atrial fibrillation). Antiplatelet therapy reduced the absolute risk of serious vascular events (non-fatal myocardial infarction, stroke, or vascular death) by 2.5%.

Aspirin remains the drug of choice for secondary prevention of stroke and other ischaemic events2

Trials included in the review above involved aspirin predominantly; this evidence makes it the principal antiplatelet drug. Aspirin 75–325 mg daily has most commonly been investigated; lower doses (75–150 mg daily) appear to be as effective and should minimise adverse effects1,3 (see below).

There are few comparative trials of newer antiplatelet agents and aspirin.

Reserve clopidogrel or dipyridamole for those unable to take aspirin

Clopidogrel 75 mg was slightly more effective than aspirin 325 mg daily in reducing a combined endpoint of ischaemic stroke, myocardial infarction or peripheral vascular disease in patients with existing cardiovascular disease (5.3% vs 5.8% per year, respectively).4 This equates to 196 patients needing to be treated with clopidogrel for one year to prevent one extra event compared to treating with aspirin.

This modest overall effect was achieved predominantly in patients with intermittent claudication; clopidogrel showed no greater efficacy in patients who had had a previous stroke or myocardial infarction.

While the efficacy and safety of clopidogrel is similar to aspirin, its use is limited by high cost (around $250 for 3-months’ PBS supply of clopidogrel versus less than $10 for aspirinA). Clopidogrel should not replace aspirin as first choice5; it should be reserved for patients who cannot tolerate, or are allergic to, aspirin.6There is no evidence that dipyridamole alone should be preferred to aspirin.1,7 Similarly, adding dipyridamole to aspirin did not conclusively reduce serious vascular events in all patients.1,6,7 Ongoing research may clarify the role of dipyridamole. 

Ticlopidine should not be used because it has an inferior adverse event profile and is no more efficacious2

Ticlopidine has been associated with haematological toxicity including neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura.6 Clopidogrel has less risk of serious adverse effects and is preferred to ticlopidine.8
A. Note: This represents PBS supply of aspirin only; costs may vary for patients buying aspirin over-the-counter.

Should aspirin be used for primary prevention of cardiovascular events?

Consider low-dose aspirin only when the absolute benefits are likely to exceed the risk of adverse events

While the benefits of aspirin are established in secondary prevention, the lower baseline risk in those without symptomatic cardiovascular disease means there is less absolute benefit to be gained. Table 1 shows how benefits increase with increasing risk of CHD events while possible adverse effects remain constant as they are independent of CHD risk.

Table 1: Estimated benefits and harms of aspirin in patients at different levels of CHD riskB 9,10

Patient’s estimated 5-year risk for CHD events at baseline
Outcome 1% 3% 5%
Effect on all-cause mortality No change No change No change
No. (95% CI) of CHD events avoided  3 (1–4) 8 (4–12) 14 (6–20)
No. of ischaemic strokes avoided 0 0 0
No. (95% CI) of haemorrhagic strokes precipitated 1 (0–2) 1 (0–2) 1 (0–2)
No. (95% CI) of major gastrointestinal bleeding events precipitated 3 (2–4) 3 (2–4) 3 (2–4)
Benefit-to-risk ratio 0.75 2.0 3.5

B. Estimates based on 1000 patients receiving aspirin for 5 years and a relative risk reduction of 28% for CHD events in those who received aspirin.

Assess cardiovascular risk using a Cardiovascular Risk Calculator

In patients without cardiovascular disease, aspirin appears to reduce myocardial infarction but has no effect on ischaemic stroke or all-cause mortality over 5 years.9

Thus, as with secondary prevention, those at highest risk show the greatest benefit-to-risk ratio for taking aspirin.

Adverse effects of aspirin

Aspirin is associated with upper gastrointestinal bleeding and haemorrhagic stroke

The main adverse effects of concern with aspirin are gastrointestinal bleeding and intracranial haemorrhage.

When aspirin is used as secondary prevention, the benefits of reducing the rate of serious vascular events clearly outweigh the risks of adverse effects. However, this relative advantage diminishes as the patient’s risk of a CHD event decreases (see the 1% risk patient group in Table 1).

Adverse effects with aspirin are dose-related and can occur at low doses

While adverse effects with aspirin are dose dependent, even the low doses used for cardiovascular prophylaxis carry an increased risk of gastrointestinal bleeding11,12 or intracranial haemorrhage.13

There is no evidence to support the notion that specific formulations of aspirin (e.g. buffered or enteric coated) modify the risk of gastrointestinal bleeding.11,12

Warfarin underused to prevent thromboembolism in atrial fibrillation

Thromboembolism is the main hazard arising from atrial fibrillation (AF). Warfarin substantially reduces the risk of stroke in AF14,15 and has a role in both primary and secondary prevention.3,14,15 The benefit conferred depends on the individual risk of thromboembolism.

  • Assess the risk of thromboembolism/stroke in all patients with AF
  • Warfarin substantially reduces the risk of stroke in AF in primary and secondary prevention
  • Aspirin provides only around one-third the benefit of warfarin in high-risk AF patients3
  • At low levels of risk, the likelihood of stroke is similar to that of bleeding on warfarin (1–3%). Aspirin is an alternative in such low-risk patients or where warfarin is contra-indicatedRisk of stroke in atrial fibrillation

Warfarin monitoring, INRC targets, and the elderly

Assess risks and benefits of warfarin therapy and review regularly

For patients who are not anticoagulated, review stroke risk and possible benefit of warfarin annually.

For patients using warfarin, assess bleeding risk regularly. Factors which affect the decision to anticoagulate17:

  • the magnitude of bleeding risks and other contra-indications
  • concurrent medications or diseases that increase bleeding risk or interfere with anticoagulation control
  • likely drug and monitoring compliance.
C. INR = International normalised ratio.

An INR of 2.0–3.0 is appropriate for AF and most other conditions

An INR of 2.0–3.0 is appropriate for AF and most other conditions. Higher ranges are specified occasionally, as in people with prosthetic heart valves.18

Lower INR targets (e.g. INR = 2) may be justified in some older patients at a higher risk of bleeding.16 However, as the INR decreases below 2.0, the risk of thromboembolic stroke increases.19

Bleeding risk increases with17,20:

  • Age > 75 years
  • Instability of INR control
  • INR > 3
  • Drug interactions that increase INR
  • Co-morbidities (e.g. uncontrolled hypertension, cerebrovascular or peripheral vascular disease, liver disease, gastrointestinal or cerebral haemorrhage, coagulation defects)
  • Social factors (e.g. excessive alcohol consumption, forgetfulness)

Warfarin has many known and potential drug interactions

If there is an unstable anticoagulant effect or unexpected INR result, investigate potential sources of interactions, including

  • medication commenced by another practitioner (e.g. dentist, specialist, etc.)
  • non-prescribed medicines (OTCs, complementary medicines, vitamins and nutritional supplements)
  • changes in diet or alcohol consumption.

Inform the consumer to seek advice before commencing any new medicine or health product

Check INR within 2 to 7 days of commencing any new medicine, including periods of increased paracetamol use (e.g. 2–4 g daily), or with changes in health.3

Reference sources such as the Australian Medicines Handbook 2003 provide details of clinically relevant interactions with warfarin.

Patient participation and education are critical in choosing and using warfarin

Involving patients in discussions about the relative benefits and risks of warfarin therapy should aid compliance and safety. Consider the individual’s ability and willingness to cope with monitoring requirements. Patient information bookletsare available from manufacturers of warfarin, pharmacies, hospital clinics, and in Medical Director software.

For more information about warfarin, including potential interactions with complementary medicines, see NPS News 30.

Expert reviewers

Professor Alex Gallus. Professor of Haematology and Director of Pathology Services Flinders Medical Centre and Repatriation General Hospital, Adelaide, SA

References
  1. Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86.
  2. NSW TAG. Antiplatelet therapies. December 2000. (Available from www.nswtag.org.au Accessed August 2003).
  3. CAPRIE Steering Committee. Lancet 1996;348:1329–39.
  4. Hankey GJ, et al. Stroke 2000;31:1779–84.
  5. Hankey GJ, Eikelboom JW. Med J Aust 2003;178:568–74.
  6. De Schryver ELLM, et al. Stroke 2003;34:2072–80.
  7. Australian Medicines Handbook 2003.
  8. Hayden M, et al. Ann Intern Med 2002;136:161–72.
  9. Hung J. Med J Aust 2003;179:147–52.
  10. Derry S, Loke YK. BMJ 2000;321:1183–7.
  11. Garcia Rodriguez LA, et al. Br J Clin Pharmacol 2001;52:563–71.
  12. He J, et al. JAMA 1998;280:1930–5.
  13. Hart RG, et al. Ann Intern Med 1999;131:492–501.
  14. Segal JB, et al. Anticoagulants or antiplatelet therapy for non-rheumatic atrial fibrillation and flutter. In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software
  15. Therapeutic Guidelines: Cardiovascular. Version 4, 2003.
  16. American College of Cardiology/American Heart Association/European Society of Cardiology. Pocket guidelines: management of patients with atrial fibrillation. 2002 (Available from www.acc.org Accessed August 2003).
  17. Fitzmaurice DA, et al. BMJ 2002;325:828–31.
  18. Gallus AS, et al. Med J Aust 2000;172:600–5.
  19. Hylek E, et al. N Engl J Med 2003;349:1019–26.
  20. Hart RG, et al. Ann Intern Med 1999;131:688–95.