Guideline 36: Antithrombotic Therapy

Antithrombotic Therapy
Section 5: Ischaemic heart disease

5.1 Myocardial infarction

5.1.1 ASPIRIN AND OTHER ANTIPLATELETS

Ten randomised trials and meta-analyses^{7,
9} have shown that antiplatelet treatment (aspirin) for one month in patients with acute myocardial infarction results in a 3.8% absolute risk difference of myocardial infarction, stroke or vascular death over one month (see Table 1). Most of the evidence comes from one large trial using 150 mg/day, which showed an additive benefit to thrombolysis with streptokinase for mortality, and maintenance of benefit for four years.⁹¹ Evidence level Ia and Ib

Routine use of aspirin is supported by many expert groups.^{2, 6,
7, 9, 92} Sequential clinical audit has shown a significant improvement in the percentage of GPs who carry aspirin so that therapy can be initiated at diagnosis.¹⁵ Evidence level III and IV

It is strongly recommended that all patients with clinically suspected evolving acute myocardial infarction who are not already receiving aspirin should be given aspirin (150-300 mg).

All general practitioners should carry aspirin so that treatment can be initiated at diagnosis.

In patients already taking aspirin, it should be continued at a dose of 150-300 mg/day.

To achieve rapid inhibition of platelet function, the aspirin tablets should not be enteric-coated, and should be swallowed as soon as possible.

Meta-analyses of 12 randomised controlled trials ^{7, 9} have demonstrated that aspirin is effective as secondary prophylaxis of cardiovascular events following acute myocardial infarction.^{9,
92} Antiplatelet treatment for one year results in a 3.5% absolute risk difference for myocardial infarction, stroke or vascular death (see Table 1). Evidence level Ia

Clopidogrel appears to be as effective as aspirin for prophylaxis of cardiovascular events following myocardial infarction.⁹³ Dipyridamole plus aspirin shows similar efficacy to aspirin alone.⁷ Evidence level Ib

It is strongly recommended that aspirin (75-300 mg) be continued long term in survivors of myocardial infarction.

Clopidogrel (75 mg/day) is an effective alternative in patients with contraindications to aspirin, or who are intolerant of aspirin.

Randomised controlled trials have shown that warfarin is also effective in secondary prophylaxis of cardiovascular events after myocardial infarction.^{94,
95, 96,
97, 98,
99} but is more complicated to manage and has a higher risk of bleeding than antiplatelet agents. Conjoint use of warfarin and aspirin increases the risk of bleeding.^{14,
92} Aspirin should therefore be discontinued in warfarinised patients. Evidence level Ib

Aspirin may be continued in heparinised patients with acute myocardial infarction (see below), but should be discontinued in patients receiving warfarin for ischaemic heart disease.

5.1.2 THROMBOLYTICS

Meta-analyses of randomised controlled trials have shown that thrombolysis in selected patients reduced mortality in acute myocardial infarction.^{27,
100} Evidence level Ia

It is strongly recommended that all patients with clinically suspected evolving acute myocardial infarction be considered for thrombolytic therapy.

Thrombolysis should be used concurrently with aspirin, which has an additive effect.⁹¹

Scottish,² UK,²⁸ and North American¹⁰⁰ guidelines have been published.

5.1.3 ANTICOAGULANTS

A meta-analysis of randomised trials¹⁰¹ has shown that routine intravenous or subcutaneous heparin reduces mortality in suspected acute myocardial infarction by about 25% in the absence of aspirin; and by about 6% in the presence of aspirin, at the cost of increased bleeding (about 3% increase in major bleeds). Many trials also predated the routine use of thrombolytics, which also reduces the additional benefit of heparin.^{95, 101} Evidence level Ia and Ib

Heparin should not be used routinely in addition to aspirin in acute myocardial infarction, but reserved for patients at increased thromboembolic risk.

Trials of low molecular weight heparins in acute myocardial infarction are in progress.

Intravenous heparin is commonly given during and following thrombolysis with alteplase to reduce the risk of early coronary rethrombosis.^{28,
100, 102} The usual dose of heparin is an intravenous bolus infusion (5,000 IU) when commencing alteplase, continuing for 48 hours at an initial rate of 1,000 IU/h, titrated to maintain a target APTT ratio of 1.5-2.0. Use of a nomogram for dose adjustment may improve the achievement of target APTT ratios.¹⁰² However, the risks and benefits of adding heparin to thrombolytic therapy should be carefully considered,¹⁰¹ especially the risk of haemorrhagic stroke.

Patients with acute, established myocardial infarction at increased risk of systemic or pulmonary thromboembolism due to:

large anterior Q-wave infarction
severe left ventricular dysfunction
congestive heart failure
history of systemic or pulmonary embolism or thrombophilia
echocardiographic evidence of mural thrombus
persistent atrial fibrillation
prolonged immobilisation
marked obesity

should be considered for anticoagulation with full-dose heparin (target APTT ratio 2.0, range 1.5-2.5) followed (if indicated by continuing risk) with warfarin (target INR 2.5, range 2.0-3.0) for up to three months, depending upon the physician's estimate of the risk : benefit ratio in the individual patient

Based on meta-analysis of randomised trials,¹⁰¹ and on additional long-term trials in atrial fibrillation ^{5,
10, 11,
12, 17,
19} (see section 3)

The duration and intensity of anticoagulation will depend on the clinical course, and will also be influenced by echocardiographic findings.

Meta-analyses of randomised controlled studies have shown a reduction in deep vein thrombosis in acute myocardial infarction by low-dose subcutaneous heparin.^{92,
101} Evidence level Ia

In other patients with acute myocardial infarction, and in patients as defined above in whom the bleeding risks of full-dose anticoagulation are judged to outweigh the benefits, prophylaxis of venous thromboembolism with low-dose subcutaneous heparin (7,500 IU 12-hourly) for 7 days or until ambulant, should be considered.

In patients in whom the bleeding risks of low-dose heparin are judged to outweigh the benefits, graduated elastic compression stockings or intermittent pneumatic compression should be considered for prophylaxis of venous thromboembolism.

Recommendation based on extrapolation of data from trials in other hospital patient groups.⁵

Randomised controlled trials have shown that warfarin is similarly effective to aspirin in secondary prophylaxis of cardiovascular events.^{92,
94, 95,
96, 97,
98, 99} Evidence level Ib

For long term prophylaxis of arterial events following myocardial infarction, antiplatelet agents (usually aspirin) are usually preferred to warfarin because of their lower complexity, bleeding risk, and cost.

Long term warfarin (target INR 2.5, range 2.0-3.0) should be considered instead of aspirin in patients with persistent atrial fibrillation and heart failure or left ventricular dysfunction (see section 3).

5.2 Unstable angina

Meta-analyses of 12 randomised controlled studies have shown that antiplatelet agents, usually aspirin (75-1300 mg/day) reduce the risk of myocardial infarction, stroke or vascular death (absolute risk difference 5.5% over 18 months) ^{7,
9, 92} (see Table 1). Evidence level Ia

It is strongly recommended that all patients with clinically suspected unstable angina should receive aspirin (150-300 mg/day) as soon as possible.

This should be continued long term as prophylaxis of cardiovascular events (75-300 mg/day).

A meta-analysis of six randomised controlled trials has shown that full-dose intravenous heparin, in addition to aspirin, further reduces the risk of myocardial infarction or death.¹⁰³ Evidence level Ia

It is strongly recommended that all patients who are hospitalised with severe unstable angina should receive in addition to aspirin full-dose heparin (target APTT ratio 2.0, range 1.5-2.5), which should be maintained for 3-4 days, or until resolution of unstable angina.

Alternatively, LMW heparin (enoxaparin or dalteparin) can be given. ^{104,
105, 106}

Recent trials indicate that platelet glycoprotein IIb/IIIa inhibitors (e.g. abciximab) are also effective.^{107,
108, 109} Evidence level Ib

A meta-analysis of randomised trials has shown an increased rate of death and myocardial infarction for thrombolytic therapy in unstable angina.¹¹⁰ Hence, this is not routinely recommended. Evidence level Ia

5.3 Stable angina

Six randomised controlled studies and meta-analyses have shown that aspirin reduces the risk of cardiovascular events (absolute risk difference 4.5% over 33 months)^{7,
9, 92} (see Table 1). Evidence level Ia and Ib

Patients with stable angina should receive aspirin (75-300 mg/day) long term as prophylaxis of cardiovascular events.

5.4 Coronary angioplasty, stents and bypass grafts

Meta-analyses of randomised controlled studies have shown improved maintenance of graft or arterial patency and reduction in cardiovascular events following aspirin therapy.^{7,
8, 9, 111,
112} Evidence level Ia

Aspirin use prior to bypass grafting does not appear to increase antithrombotic efficacy, and increases perioperative bleeding,8 hence it may be discontinued one week prior to surgery. It can be commenced postoperatively (150-300 mg/day by nasogastric tube). Evidence level Ia

Aspirin (300 mg/day) should be given as antithrombotic prophylaxis, starting at least two hours prior to angioplasty, or six hours following bypass grafting (unless contraindicated by bleeding) and continued long term (75-300 mg/day).

It is standard practice to give full dose intravenous heparin prior to coronary angioplasty, and to continue this for up to 24 hours in the presence of unstable angina, complex lesions, multivessel angioplasty, or a technically suboptimal result.¹¹¹ Continued heparin therapy in unstable angina is supported by randomised studies (see section 5.3). Following placement of coronary artery stents, antiplatelet therapy with aspirin ± ticlopidine (which is not presently licensed for this indication in the UK) appears significantly superior to aspirin combined with warfarin.¹¹³ Platelet glycoprotein IIb/IIIa receptor antagonists (e.g. abciximab) may be appropriate in high risk coronary angioplasty, particularly when complicated by thrombus formation¹⁰⁵ (see the SIGN guideline on Coronary Revascularisation in the Management of Stable Angina Pectoris¹¹⁴). Evidence level Ia

It is also standard practice to heparinise systemically during cardiac bypass surgery.