Unfractionated heparin (UFH) is an anticoagulant agent used by a variety of ambulance services to treat patients suffering ST-elevation myocardial infarction (STEMI). The primary treatment objective for patients with STEMI is early coronary reperfusion, which is the restoration of blood flow to an occluded coronary artery (Barron et al, 1998: 1150). Coronary reperfusion may be achieved by primary percutaneous coronary intervention (PPCI), or by fibrinolysis through the administration of a tissue plasminogen activator (tPA). In many jurisdictions, PPCI is the preferred method of treatment for patients suffering STEMI (Giralt et al, 2015: 70). Therefore, this paper will chiefly focus on the prehospital administration of UFH prior to PPCI.
Percutaneous coronary intervention (PCI) is a mechanical procedure that treats the narrowing or obstruction of coronary arteries by combining coronary angioplasty with stenting (Heart and Stroke Foundation, 2018). Coronary angioplasty is the temporary expansion of blood vessels by inflating a surgical balloon in the affected artery to increase vessel size and improve blood flow. The insertion of a wire-meshed stent is then used to stabilise the expanded blood vessel permanently (National Heart, Lung and Blood Institute, n.d). UFH has traditionally been considered the ‘gold standard’ drug of choice to be administered prior to PPCI (van Gameren et al, 2018: 1443).
The primary effect of UFH is to activate antithrombin III—an anticoagulant produced naturally by the body (St John Ambulance New Zealand, 2018: 372). Activated antithrombin III causes the inhibition of factor Xa and thrombin, resulting in inhibition of clot formation (see also Table 1). UFH is not a fibrinolytic agent, meaning it will not dissolve a clot. However, UFH will inhibit further clot formation and progression (Watson et al, 2016: 2). The objective of this study is to review the effectiveness and safety of prehospital UFH administration to STEMI patients prior to PPCI, and to consider whether this drug should be more widely used for these purposes across international ambulance services.
| Drug | Unfractionated heparin (UFH)/heparin |
|---|---|
| Drug class | Anticoagulant |
| Mechanism of action |
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| Indications |
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| Contraindications |
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| Adverse effects |
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| Dose |
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| Route of administration |
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Sources: ACT Ambulance, 2014; Alberta Health Services EMS, 2017; Ambulance Victoria, 2018; St John Ambulance New Zealand, 2018; MIMSOnline, 2019; Queensland Ambulance Service, 2019
Methods
A literature search was conducted from August to September 2019 to identify articles relevant to prehospital UFH administration prior to PPCI. The EBSCO Host (Health) group of journal databases (which includes CINAHL), together with Medline (All), and Scopus were used for this search. Primary search terms were heparin, prehospital, and percutaneous coronary intervention, together with the related terms: paramedic* and ambulance. Subsequent searches also included the terms safety, acute myocardial infarction, and fibrinolytic therapy. Boolean operators were used to link search terms. The journal database search yield is illustrated in Figure 1.
After the journal database search had been completed, duplicate articles were removed as were articles not relevant to this study. Eleven articles were retained from the EBSCO Host search; five from the Medline search (one duplicate, and four articles were not relevant); and two from Scopus (10 articles not relevant to this study). A total of 18 journal articles were retained for this study.
Thereafter, a search of grey literature was undertaken to obtain relevant clinical practice guidelines from international ambulance services, and to identify other relevant government and non-commercial sources. Ten relevant clinical practice guideline compendiums from ambulance services were identified and retained for this study, as were two books and four relevant websites.
Results
UFH has traditionally been a drug routinely administered to STEMI patients prior to PPCI (van Gameren et al, 2018). However, this drug should continue to be examined in light of emerging evidence, technology, and the development of new pharmacological regimes. In the present review, UFH will initially be examined with respect to survival outcomes, coronary artery patency, and adverse effects.
A positive correlation exists between early administration of anticoagulant therapies (such as UFH) and survival outcomes for patients (see for example Welsh et al, 2005; Smalling et al, 2007; Giralt et al, 2015). Zijlstra et al (2002) highlight that patients treated with prehospital Aspirin and heparin immediately after STEMI diagnosis were associated with reduced mortality rates when compared with hospital-based administration of the same drugs prior to PPCI.
Coronary artery patency is often measured by thrombolysis in myocardial infarction (TIMI) grade flow, which is a scoring system for coronary blood flow assessed during PCI. The grading scale ranges from TIMI 0–3, with 0 representing the poorest grade of perfusion beyond the occluded area (Table 2). Early administration of UFH has been seen to promote artery recanalisation and improve the rates of TIMI 3 patency within the infarcted region. Zijlstra et al (2002) found that patients who received prehospital anticoagulants had an improved TIMI score immediately following PPCI when compared with patients who received the drug on hospital premises. Giralt et al (2015) made similar findings, and concluded that early UFH administration was an independent predictor of improved TIMI grade flow in STEMI patients who subsequently underwent PPCI.
| TIMI 0 | Refers to no forward moving perfusion beyond the coronary occlusion |
| TIMI 1 | Refers to a faint forward moving blood flow beyond the coronary occlusion; however, this perfusion is inadequate of the distal coronary bed |
| TIMI 2 | Refers to partial perfusion where there is sluggish forward flow and the distal bed is perfused |
| TIMI 3 | Refers to normal blood flow which completely perfuses the distal coronary bed. There is no/limited occlusion of the artery |
Source: Sarkar et al, 2019
While these findings appear positive, it is noted that UFH is associated with several adverse effects which may draw into question the utility of its prehospital use in the STEMI patient (Rubboli et al, 2007). UFH has a narrow therapeutic window, creating uncertainty as to the dose-response relationship, and the predictability of overall anticoagulant response (Giuseppe and Lansky, 2016; Liu et al, 2016; Silvain et al, 2018). In a study by Silvain et al (2012), UFH administration to STEMI patients was associated with a higher number of adverse drug reactions such as major bleeding, complications of myocardial infarction, and mortality when compared with another anticoagulant, enoxaparin. For these reasons, a greater level of post-administration monitoring is required for patients who receive UFH, compared with those who receive enoxaparin (Liu et al, 2015; Giuseppe and Lansky, 2016; Silvain et al, 2018; van Gameren et al, 2018; Zeitouni et al, 2018; White, 2019).
Heparin-induced thrombocytopenia is another potential adverse effect of UFH administration, albeit an uncommon complication (van Gameren et al, 2018: 1443). Heparin-induced thrombocytopenia more often occurs following administration of UFH when compared with enoxaparin (Zeymer et al, 2016; van Gameren et al, 2018; Zeitouni et al, 2018). In their study on anticoagulant use in PCI settings, Zeymer et al (2016: 3377) suggest that 0.5% of patients who receive UFH will experience heparin-induced thrombocytopenia compared with <0.1% for enoxaparin.
Enoxaparin is a low-molecular weight heparin; it is a derivative of UFH with chemical fragments approximately one-third the size of UFH. Similar to UFH, enoxaparin acts on antithrombin III to inhibit clot formation (Zeymer et al, 2016: 3377). However, the substantially lower molecular weight of enoxaparin reduces the amount of unwanted binding opportunities to plasma proteins and creates a more predictable anticoagulation pattern (Montalescot et al, 2011; Silvain et al, 2018). The more refined nature of enoxaparin is associated with decreased incidence of adverse effects such as thrombocytopenia and major bleeding (Diez et al, 2009).
Contrastingly, UFH in lower doses may be viewed as a safer option than enoxaparin when administered to patients with renal insufficiency, due to the way UFH is metabolised in the body (Giuseppe and Lansky, 2016). This is because at low doses, UFH is degraded in the body through saturated interaction with plasma proteins, endothelial cells and macrophages (Hirsh and Raschke, 2004). Comparatively, enoxaparin relies exclusively on renal excretion. Therefore, enoxaparin has to be used cautiously for patients with renal dysfunction in order to avoid drug accumulation and toxicity (Weitz and Weitz, 2009). UFH may also be deemed a safer drug for prehospital administration prior to PPCI, as it can be fully reversed by protamine sulphate in the event of adverse effects, including unanticipated overdose (Giuseppe and Lansky, 2016), whereas enoxaparin does not fully respond to this reversing agent. UFH is also a lower cost drug when compared with more recently developed anticoagulants such as enoxaparin (Giralt et al, 2015; Giuseppe and Lansky, 2016; Zeitouni et al, 2018). A summary of these findings has been provided in Table 3.
| Summary of findings | Supporting articles |
|---|---|
| Enoxaparin resulted in less ischaemic complications following PCI when compared with UFH (eight articles) | (Rubboli et al, 2006; Montalescot et al, 2011; Liu et al, 2015; Viikaila et al 2016; Zeymer et al, 2016; Silvain et al, 2018; Zeitouni et al, 2018; White, 2019) |
| UFH requires constant post-administration monitoring, whereas Enoxaparin does not (six articles) | (Liu et al, 2015; Giuseppe and Lansky, 2016; Silvain et al, 2018; van Gameren et al, 2018; Zeitouni et al, 2018; White, 2019) |
| Enoxaparin more frequently achieves therapeutic levels than unfractionated heparin (five articles) | (Liu et al, 2015; Zeymer et al, 2016; Silvain et al, 2018; van Gameren et al, 2018; White, 2019) |
| UFH is the preferred anticoagulant for PPCI (four articles) | Liu et al, 2015; Zeymer et al, 2016; van Gameren et al, 2018; White, 2019) |
| UFH has an unpredictable anticoagulation response (four articles) | (Silvain et al, 2012; Liu et al, 2015; Giuseppe and Lansky, 2016; Silvain et al, 2018) |
| Heparin-induced thrombocytopenia is more likely following administration of UFH than enoxaparin (three articles) | (Zeymer et al, 2016; van Gameren et al, 2018; Zeitouni et al, 2018) |
| UFH is a low-cost drug (three articles) | (Giralt et al, 2015; Giuseppe and Lansky, 2016; Zeitouni et al, 2018) |
While there is broad agreement within the literature about the efficacy of early anticoagulant administration for STEMI patients—including the prehospital administration of these agents—there is not a consensus about which anticoagulant is the most optimal choice for STEMI patients who subsequently undergo PPCI. These differences of opinion appear to be mirrored in international guidelines for paramedic practice. A review of paramedic clinical guidelines in Australia, New Zealand and the UK show that some statutory ambulance services advocate UFH administration, others enoxaparin, and still others, both UFH and enoxaparin within various prehospital STEMI treatment regimens (Table 4). It may be noted that some of these ambulance services will provide pharmacological regimes to facilitate subsequent PPCI for the STEMI patient, fibrinolysis via tPA, or both (see for example QAS, 2018).
| Paramedic guidelines (per ambulance service/jurisdiction) | Unfractionated heparin | Enoxaparin | |
|---|---|---|---|
| Australia | New South Wales Ambulance | No | Yes |
| Queensland Ambulance Service | Yes | Yes | |
| Australian Capital Territory Ambulance | Yes | No | |
| Ambulance Victoria | Yes | No | |
| South Australia Ambulance Service | No | No | |
| St John Ambulance Western Australia | Yes | No | |
| St John Ambulance Northern Territory | No | No | |
| Ambulance Tasmania | No | No | |
| New Zealand | St John New Zealand | Yes | Yes |
| Wellington Free New Zealand | Yes | Yes | |
| UK | Joint Royal Colleges Ambulance Liaison Committee (JRCALC) | Yes | No |
Includes anticoagulant used to support PPCI and/or tPA administration. Sources: NSW Ambulance, 2016; Queensland Ambulance Service, 2019; ACT Ambulance, 2014; Ambulance Victoria, 2018; South Australia Ambulance Service, 2018; St John Ambulance Western Australia, 2014; St John Ambulance Northern Territory 2013; Ambulance Tasmania, 2012; St John Ambulance New Zealand, 2018; Wellington Free Ambulance, 2019; Association of Ambulance Chief Executives, 2019
Moreover, ambulance services represent an initial link in an acute treatment regimen for the STEMI patient which must be compatible with the care delivered in emergency departments and even surgical settings. Therefore, it is likely that paramedic clinical guidelines will also be influenced by hospital-based practices in each jurisdiction.
Discussion
UFH has traditionally been the standard anticoagulant administered prior to PPCI for STEMI patients; however, the use of enoxaparin for this patient group has also received attention within the recent literature. There are differing opinions about whether UFH or enoxaparin should be the preferred anticoagulant for this patient group. UFH is associated with benefits including low cost, availability of a reversal agent, and a greater level of safety for patients with renal insufficiency. On the other hand, enoxaparin provides a more predictable anticoagulation pattern and appears to be associated with less adverse effects (such as heparin-induced thrombocytopenia).
Toward the beginning of this century, enoxaparin seemed promising as the optimal anticoagulant for patients undergoing PPCI (e.g. Murphy et al, 2007; Navarese et al, 2011). However, more recent studies show that its superiority over UFH has not been established (Zeymer et al, 2016; Liu et al, 2017; van Gameren et al, 2018; White, 2019), even though the two drugs appear otherwise comparable. To comprehensively determine which anticoagulant is most optimal for prehospital administration prior to PPCI, studies need to examine the prehospital administration of a wide range of anticoagulant regimens including UFH, enoxaparin, and newer agents such as bivalirudin and fondaparinux.
The objective of this study, however, was to review the effectiveness and safety of prehospital UFH administration to STEMI patients prior to PPCI, and to consider whether this drug should be used more widely for these purposes across international ambulance services. It is clear from this study that prehospital UFH administration is absolutely appropriate and should be considered as part of a prehospital treatment regimen for STEMI patients who will subsequently undergo PPCI.
Conclusion
A review of current literature unequivocally demonstrates that routine early anticoagulant administration is beneficial for STEMI patients who subsequently undergo PPCI, and it is on this basis that anticoagulant drug regimens for these patients must be more widely considered by international ambulance services.
There has been recent debate about which anticoagulant drug is the most optimal for STEMI patients who subsequently undergo PPCI. These debates are likely to continue, and even widen, as new drugs and technology are made available. At the present time, however, what appears most important is that an anticoagulant—such as UFH or, in some jurisdictions, enoxaparin—should be strongly considered by international ambulance services as a standard feature of prehospital treatment regimens for STEMI patients who will subsequently undergo PPCI.