17.1. Introduction

STEMI management has evolved rapidly over recent years with the introduction of several new pharmacological and interventional therapies. Some of these therapies have been the subject of NICE Technology Appraisals (TA) or have been considered in other Clinical Guidelines (CG). To avoid duplication the GDG did not review any evidence for these therapies as part of this guideline.

The scope for the STEMI guideline states that the recommendations from TA230 (bivalirudin) and TA236 (ticagrelor) should be incorporated into the guideline. This chapter sets the context for this and also identifies other related NICE guidance. The guidance documents relating to pharmacological interventions included in this chapter are shown in Table 79.

Table 79

NICE guidance relevant to the pharmacological aspects of the STEMI guideline.

Clinicians should be aware that pharmacological therapy of people with STEMI is complex and generally involves multiple drugs that affect coagulation (antithrombotics). The specific choice of drugs will depend on licensed indications and individual clinical circumstances, and the relative efficacy and safety (especially bleeding risk) of different drug combinations are influenced by the pharmacology, dosing, and timing of administration of the different agents. In addition, only certain combinations of these drugs have been tested in randomised clinical trials. Integrating the information from these trials into clinical practice is a major challenge in the management of people with STEMI.

17.2. Aspirin

Aspirin has an antithrombotic effect caused by irreversible inhibition of platelet thromboxane A2 production. Aspirin is an established treatment for people with acute coronary syndrome including people with STEMI.^5,193,195

Clinical Guideline CG95²³⁰ (Chest pain of recent onset) recommends that all people in whom acute coronary syndrome is suspected should be offered a single loading dose of aspirin 300mg as soon as possible, unless there is clear evidence that they are allergic to it. If aspirin is given before arrival at hospital, a written record that it has been given should be sent with the person.

Following reperfusion therapy for STEMI, treatment with aspirin should be continued in line with CG48 myocardial infarction secondary prevention (an update of CG48 is due for publication in November 2013).²¹⁹

17.3. Clopidogrel

Clopidogrel is an oral thienopyridine, which exerts its antithrombotic effect by inhibiting platelet activation via irreversible binding of an active metabolite to the P2Y₁₂ adenosine diphosphate (ADP) platelet receptor. Clopidogrel is licensed for the prevention of atherothrombotic events in adult people suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.

The GDG considered that treatment with clopidogrel is an established option in the pharmacological treatment of people with acute STEMI including people undergoing PPCI. The GDG were aware that a clopidogrel loading dose of 600mg is not licensed in the UK but is used widely in current practice, especially in people undergoing PPCI.

17.4. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention

Prasugrel is an oral thienopyridine, which exerts its antithrombotic effect by inhibiting the platelet P2Y₁₂ ADP receptor more rapidly and potently than clopidogrel.

Prasugrel, co-administered with aspirin, is licensed for the prevention of atherothrombotic events in people with acute coronary syndrome (unstable angina, non-ST-segment-elevation myocardial infarction, or ST-segment-elevation myocardial infarction) undergoing primary or delayed percutaneous coronary intervention.

TA 182²²³ (Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention) evaluated the role of prasugrel in the management of people with acute coronary syndrome scheduled to undergo PCI. TA182 recommended prasugrel in combination with aspirin as an option for preventing atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when:

• immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is necessary or
• stent thrombosis has occurred during clopidogrel treatment or the person has diabetes mellitus.

In TA182 a health economic model submitted by the manufacturer compared prasugrel with proprietary clopidogrel (as Plavix). The 1-year cost of proprietary clopidogrel was estimated at £464.05 (based on £1.26 per day). Following publication of TA182 in October 2009 the availability of generic clopidogrel has substantially reduced the cost of treatment. The health economic analysis that underpins the recommendation in TA 182 is therefore outdated and the cost effectiveness of prasugrel relative to generic clopidogrel is uncertain.

Following consultation NICE Guidance Executive has decided that a review of TA182 should be planned into the appraisal work programme and hence TA182 is undergoing update, publication expected August 2014.²²³

The GDG noted that TA182 was based on the TRITON–TIMI 38 trial, which compared prasugrel with clopidogrel (using a clopidogrel loading dose of 300mg) in people with acute coronary syndrome scheduled to undergo PCI. In this trial adjunctive medical therapy and device selection were at the discretion of the physician. Unfractionated heparin was administered to 73% of people treated by PPCI but other antithrombins (for example fondaparinux, bivalirudin) were used infrequently.^199,333 The GDG considered that evidence for the use of prasugrel in people with acute coronary syndrome scheduled to undergo PCI is predicated on background treatment with aspirin, heparin, and a GPI if required.

17.5. Ticagrelor for the treatment of ACS

Ticagrelor exerts its antithrombotic effect by reversible inhibition of the platelet P2Y₁₂ ADP receptor.

Ticagrelor, co-administered with low-dose aspirin, is licensed for the prevention of atherothrombotic events in adults with acute coronary syndrome, including people with STEMI and people who are treated by PPCI.

TA236²²⁶ (Ticagrelor for the treatment of acute coronary syndromes) evaluated the role of ticagrelor in the management of people with acute coronary syndrome. In a health economic analysis ticagrelor was found to be cost effective relative to generic clopidogrel (cost of clopidogrel 30-pack = £3.40). TA236 recommends ticagrelor as an option in people with STEMI that cardiologists intend to treat by PPCI. When selecting an ADP receptor antagonist clinicians should be aware that evidence for the use of ticagrelor relates to people who were also treated with aspirin, unfractionated or low-molecular weight heparin, and a GPI if required.

The GDG noted that TA236 is based on an analysis of the PLATO trial of ticagrelor versus clopidogrel in people with acute coronary syndrome. The loading dose of clopidogrel varied but most people were given 300–375mg. The choice of antithrombin was at the discretion of the operator and unfractionated or low-molecular weight heparin was administered in the majority of cases. Bivalirudin or fondaparinux were used in less than 2% of people. A GPI was administered to over one-third of the participants.^284,323 The GDG considered that evidence for the use of ticagrelor in people with acute coronary syndrome, including people with STEMI, is predicated on background treatment with aspirin, heparin, and a GPI if required.

17.6. Bivalirudin for the treatment of STEMI

Bivalirudin is a synthetic 20-amino acid polypeptide analogue of hirudin, which exerts its antithrombotic effect by directly inhibiting soluble and clot-bound thrombin. Bivalirudin has a short half-life and is administered by intravenous infusion.

Bivalirudin has a marketing authorisation as an anticoagulant in adults undergoing PCI, including people with STEMI undergoing primary PCI. The summary of product characteristics (SPC) states that bivalirudin should be administered with aspirin and clopidogrel. The use of bivalirudin in combination with prasugrel or ticagrelor is outside the marketing authorisation for bivalirudin.

TA230²³⁴ (Bivalirudin for the treatment of STEMI) evaluated the role of bivalirudin in people with STEMI undergoing PPCI. In a health economic analysis based on the HORIZONS-AMI trial, bivalirudin dominated the combination of heparin and GPI (that is, bivalirudin was less costly and more effective). TA230 recommends bivalirudin in combination with aspirin and clopidogrel for the treatment of adults with STEMI undergoing PPCI.

The GDG noted that 71% of all participants in HORIZONS-AMI were given pre-procedural heparin. Within the bivalirudin group, people treated with pre-procedural heparin had a lower rate of major adverse cardiovascular events than those who did not receive pre-procedural heparin, but there was no statistically significant interaction between treatment group and pre-procedural heparin.

The GDG also noted that HORIZONS-AMI compared bivalirudin with unfractionated heparin and routine GPI. The efficacy and cost effectiveness of bivalirudin versus heparin and selective use of GPI has not been determined, particularly when administered with a high loading dose of clopidogrel. In the UK the use of GPI in people undergoing PPCI in the UK has declined but in 2011 45.6% were given a GPI alone, 8.5% were given bivalirudin alone, and 7.1% were given both agents. ¹⁸³

17.7. Antithrombins in people who have been given prasugrel or ticagrelor

17.8. Glycoprotein IIb/IIIa inhibitors

Glycoprotein IIb/IIIa inhibitors (GPIs) are antagonists of the platelet glycoprotein IIb/IIIa receptor and prevent binding of platelets to fibrinogen. GPIs are potent inhibitors of platelet aggregation that have been shown to reduce the incidence of ischaemic events in people undergoing PCI, especially in people with acute coronary syndromes (ACS).

The GPIs include abciximab (a monoclonal antibody fragment), eptifibatide (a cyclic heptapeptide), and tirofiban (a peptide-mimetic inhibitor). Abciximab is licensed for the prevention of ischaemic cardiac complications in people undergoing percutaneous coronary intervention. Eptifibatide and tirofiban are licensed to prevent early myocardial infarction in adults presenting with unstable angina or non-Q-wave myocardial infarction and are intended for use with acetylsalicylic acid and unfractionated heparin, but these drugs do not have a license for use in people with STEMI.

TA47²¹¹ (Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes) was published in September 2002. CG94 (Unstable angina and NSTEMI) partially updated recommendations in TA47 on the use of GPI in people with non-ST-segment elevation acute coronary syndrome but did not consider the use of GPI in people with STEMI.²²⁹

The GDG were aware that a number of trials have assessed the role of GPIs in people with acute STEMI, both with and without pre-treatment with clopidogrel. In the UK 52.7% of people undergoing PPCI during 2011 were given a GPI.²⁷⁴ The GDG was not commissioned to update TA47 for people with STEMI and the TA is currently on the static list.

17.9. Myocardial infarction – thrombolysis

Intravenous fibrinolytic drugs are administered to people with evolving STEMI to restore coronary artery patency and limit the extent of myocardial damage. Streptokinase was the first fibrinolytic agent to be used for the treatment of STEMI, but has to be administered by intravenous infusion over 1 hour and is associated with hypotension, infrequent allergic reactions, and rarely, anaphylaxis. People treated with streptokinase may develop antibodies that neutralise the drug if repeat treatment is needed and people are therefore usually treated with streptokinase only once.

Fibrin-specific fibrinolytic drugs (alteplase, reteplase, tenecteplase) were subsequently introduced into clinical practice and shown to have advantages over streptokinase.³⁰⁰ Fibrin-specific fibrinolytic agents do not stimulate antibody production and are administered by intravenous infusion (alteplase) or by bolus injection (reteplase and tenecteplase). Fibrin-specific agents have therefore largely replaced streptokinase in UK practice, and drugs administered by bolus injection are used preferentially for pre-hospital fibrinolysis.

TA52 (Guidance on the use of drugs for early thrombolysis in the treatment of acute myocardial infarction) was published in October 2002.²¹⁰ TA52 reviewed evidence for the use of fibrinolytic drugs early in the course of STEMI. TA52 recommended streptokinase as an option for the in-hospital treatment of STEMI for people who have not previously been given streptokinase, but reteplase and tenecteplase were preferred for pre-hospital treatment. TA52 states that heparin (an anticoagulant) is given with all fibrinolytic drugs except streptokinase.

The GDG noted that recommendations within TA52 were made in relation to the use of the fibrinolytic drugs in hospital and pre-hospital settings. The guidance does not directly compare hospital and pre-hospital models of delivering fibrinolysis. In current clinical practice reperfusion services based around fibrinolysis will be aiming to deliver a fibrinolytic drug and an anticoagulant as soon as possible after presentation with STEMI and this is likely to involve pre-hospital treatment. The GDG therefore considered that reperfusion services are likely to select a single fibrin-specific bolus fibrinolytic agent (reteplase or tenecteplase) and an anticoagulant for the limited number of people eligible for this therapy, regardless of the location where therapy is initiated. Pre-hospital fibrinolytic therapy and concomitant administration of antithrombin is considered elsewhere in this guideline (Chapters 13, and 14).

The GDG noted that the cost of fibrin-specific agents has fallen since TA52 was published and in the UK the introduction of primary PPCI services has led to a rapid decline in the use of fibrinolytic therapy. The cost impact of using fibrin-specific agents for all people offered fibrinolytic therapy in England would therefore be small.

17.10. Other related NICE Guidance

In addition to the recommendations incorporated within the STEMI guideline, the GDG noted the importance of other related NICE guidance particularly in relation to life style modification, secondary prevention therapy, medicines adherence, cardiac rehabilitation and discharge planning.

The GDG were also mindful of recommendations within the Patient Experience guideline (CG138²⁴¹) relating to information provision and discussions about risks and benefits of treatment. In particular, recommendations pertaining to people who remain unconscious following cardiac arrest and who are unable to indicate their consent to treatment were highly relevant.

The GDG made the following recommendation:

Table A

Related NICE guidance for people who have had an acute STEMI.