Principal Developer: A. Roussin
Secondary Developers: J. Bormanis, M. Green, J. Lam

Background

Thrombosis plays a major role in ischemic heart disease. Patients who have sustained an acute myocardial infarction are at increased risk of developing vascular events such as sudden death, recurrence of infarction and thromboembolic stroke. The results of recent clinical studies indicate that antithrombotic therapy significantly reduces the number of vascular events in these patients. The time course of anticoagulation or antiplatelet therapy varies whether the patient has received thrombolysis or not. The antithrombotic therapy during the hospital phase of MI is beyond the scope of this guideline.

Epidemiology

Following the recovery of an acute MI, patients remain at increased risk of sustaining subsequent thromboembolic complications or death for many years.

The risk of having a recurrent MI is approximately 15-20 % in the 2 to 3 years following a myocardial infarction.

The risk of stroke ranges generally from 1% to 3% but in some patients may be as high as 6% per year. The risk increases mainly with the extent of left ventricular dysfunction and with presence of atrial fibrillation.

Anticoagulants vs Placebo post-MI  (without risk stratification)

Three trials (Sixty Plus reinfarction studies, WARIS and ASPECT) comparing placebo with oral anticoagulants have yielded greater risk reductions of stroke and reinfarction but the mortality reduction was similar. These studies targeted an INR between 2.7 to 4.5 (Sixty +) or between 2.8 to 4.8 (WARIS and ASPECT): risk stratification in those two last trials was not detailed.

Antiplatelets or Oral anticoagulants (without risk stratification)

A comprehensive meta-analysis published in 1999 by Dr Anand and Yusuf reviewed the available data up to 1998 concerning patients after an acute MI (STEMI and non-STEMI) or after a CABG. Since that time, 4 major studies have added to the gathered evidence and have led to a joint 2003 AHA/ACC Scientific Statement on Warfarin therapy under the guidance of Doctors Hirsh, Fuster, Ansell and Halperin. The recommendations pertaining to myocardial infarction can be summarized as follows:

• High-intensity oral anticoagulation (INR 3.0 to 4.0) is more effective than aspirin but is associated with more bleeding
• The combination of aspirin and moderate-intensity warfarin (INR 2.0 to 3) is more effective than aspirin but is associated with a greater risk of bleeding
• The combination of aspirin and moderate intensity warfarin (INR 2.0 to 3.0) is as effective as high intensity warfarin and is associated with a similar risk of bleeding
• The contemporary trials have not addressed the effectiveness of moderate-intensity warfarin (INR 2.0 to 3.0) and in the absence of direct evidence, it cannot be assumed that moderate-intensity warfarin is any more effective than aspirin in preventing death or reinfarction
• There is no evidence that the combination of aspirin and low-intensity warfarin (INR 2.0) is more effective than aspirin alone despite the fact that the combination produces more bleeding

Risk Stratification and Treatment Strategy

Highest risk of embolization:

• Persistent atrial fibrillation
• LV thrombus
• Previous systemic or pulmonary embolism

Warfarin therapy at INR 2.0-3.0 (target 2.5) for at least 3 months or long term (AF) Class I AHA recommendation

High risk of embolization:

• Extensive wall motion abnormalities (Class IIa AHA recommendation)
• Paroxysmal AF (Class IIa AHA recommendation)
• Severe LV systolic dysfunction with or without CHF: evidence less well established (Class IIb AHA recommendation)

Warfarin therapy at INR 2.0-3.0 (target 2.5) for at least 3 months or long term (AF)

ST-elevation MI with otherwise Low risk of embolization:

Long-term aspirin therapy (75-325 mg/day)

Clopidogrel for patients allergic or intolerant to ASA: Clopidogrel, more expensive than ASA, has been shown to be 8.7% better than ASA in reducing the combined incidence of MI, stroke and vascular mortality, mainly by reducing MI, in patients having suffered from a stroke or a MI or presenting peripheral arterial disease.

Non ST-elevation MI with otherwise Low risk of embolization:

Combination of Clopidogrel with low dose ASA for at least one year, then ASA long term

Risk Versus Benefits

Major bleeding occurs in less than 2% of the patients treated with oral anticoagulants or antiplatelets per year. The risk of bleeding is associated with the intensity of anticoagulation, ASA dosage, combined use of aspirin and oral anticoagulants and underlying disorders.

The clinical benefits of chronic antithrombotic therapy in post-MI patients far outweigh potential side-effects. Therefore, as a general rule, when a patient presents with an MI, one must consider anticoagulation or antiplatelet therapy, based on the clinical risk of thromboembolism and the scientific information available to date.

Initiation made easier (with or without heparin)

• Start with warfarin 5 mg the two first days
• Maintain INR 2.0-3.0: target of 2.5 in most circumstances
• If INR value outside therapeutic range and no signs or symptoms of thromboembolic complications or bleeding, have INR done again in 3 days. If necessary, then adjust the dosage +/- 1 mg.
• Since numerous medication and dietary changes are common post-MI, frequent monitoring (never more than 4 week intervals) should be observed.

Contraindications to Aspirin

• Active gastrointestinal blood loss
• Active peptic ulcer disease (consider clopidogrel once treated)
• Hypersensitivity (consider clopidogrel)
• Bleeding disorders
• Gastrointestinal intolerance to ASA (consider clopidogrel)

Contraindications to Warfarin

• Pregnancy, especially 6th to 10th first weeks
• Haemorrhagic tendencies
• Recent surgery to CNS, eyes, large surfaces, especially within a week
• Inadequate monitoring facilities
• Unreliable patient or circumstances
• Malignant hypertension (Refer to CPS for more information)

Safety of Warfarin Therapy

Bleeding is the most important complication of anticoagulant therapy. The intensity of anticoagulation, the concomitant use of ASA, non COX-2 NSAIDs and the underlying clinical disorder are major factors influencing the risk of bleeding.

Drug interactions are the commonest cause of significant change in the INR value. Patients should be informed not to change any medication without a physician's or pharmacist's advice. Adequate monitoring is the key to a successful and safe warfarin therapy. Please refer to the TIGC guideline on warfarin therapy.

References

1. Smith P, et al. NEJM 1990; 323(3): 147-152. (WARIS study)
2. ASPECT Research Group. Lancet 1994; 343: 499-503
3. CAPRIE. Lancet 1996; 348:1329-1349
4. Coumadin, Aspirin, Reinfarction Study (CARS) Investigators. Lancet 1997; 350:389-396
5. Anand SS, Yusuf S. JAMA 1999; 282 (21): 2058-67 (Meta-analysis)
6. 1999 Update: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction. Circulation. 1999; 100: 1016-1030 http://circ.ahajournals.org/cgi/content/full/100/9/1016
7. Sixth ACCP Consensus Conference on Antithrombotic Therapy.
   http://www.chestjournal.org/content/vol119/1_suppl/
8. CURE study. N Engl J Med 2001;345: 494-502.
9. Antithrombotic Trialists' Collaboration. BMJ 2002; 324:71–86.
10. Hurle M et al. Warfarin, aspirin, or both after myocardial infarction. NEJM 2002; 347: 969-974 (WARIS II)
11. Fiore LD et al. Department of Veterans Affairs Cooperative Studies Program Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation 2002; 105: 557-563
12. van Es RF et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised trial. Lancet 2002; 360: 109-113
13. Brouwer MA et al. Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APROCOT)-2 Trial. Circulation 2002: 106: 659-665
14. Hirsh J, Fuster V, Ansell J, Halperin J L. Circulation. 2003; 107:1692–1711. (AHA/ACC Scientific Statement)