Anticoagulation module 2: antiplatelet therapy

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Introduction

Module 1 introduced the physiology and pathology of thrombosis: how platelets and soluble coagulation proteins come together to minimise blood loss in the formation of a clot. Ideally, this process (haemostasis) is highly regulated to ensure that clots develop only under defined circumstances and only in appropriate anatomical locations. However, failure to correctly regulate haemostasis can lead to inappropriate thrombus formation.

According the National Institute for Health and Care Excellence (NICE), each year in the UK almost a quarter of a million people have a first ischaemic stroke or myocardial infarction (MI). In the UK, over 1.4 million people have had a heart attack, and 900,000 are living with the effect of stroke. About 20% of the UK population aged 55–75 years (850,000 people) have lower extremity peripheral artery disease, while 16% of people with cardiovascular disease have multi-vascular disease. We have seen in module 1 that when thrombosis occurs in an artery, it usually does so at a point where the vessel is affected by atherosclerosis, and under conditions of high shear. This means that platelets take a lead role in the initiation of arterial thrombosis, and therefore that inhibition of platelet function is central to the treatment and prevention of arterial thrombotic events. It is worth noting that each of the four major risk factors for cardiovascular disease (smoking, dyslipidaemia, diabetes and hypertension) has been independently associated with increased platelet activity.

The platelet

An understanding of platelet structure and the process of platelet activation is helpful when considering the various ways in which platelets can be suppressed pharmacologically. We have looked at these in some detail in module 1 – a summary, with an emphasis on the main pharmacological targets, is presented below.

At present, inhibitors of platelet function can be broadly grouped into three according to their mechanism of action:

  • Inhibitors of the metabolism of the cell
  • Adenosine diphosphate (ADP) receptor blockers.
  • Inhibitors of platelet–platelet interactions.

Metabolic inhibitors

There are two major drugs in this class, aspirin and dipyridamole, and both are taken orally. Aspirin is actually three drugs for the price of one, with analgesic, antipyrexial and anti-inflammatory activity, the latter accounting for its effect on the platelet.

Aspirin

Aspirin passively crosses the membrane and irreversibly inhibits cyclooxygenase by acetylation of the amino acids adjacent to the active site. The cyclooxygenase enzyme performs the rate-limiting step in synthesis of thromboxane A2 from arachidonic acid (see figure 1).

Figure 1. Mechanism of action for aspirin
Figure 1. Key elements of platelet function, showing current pharmacological targets

Without a nucleus, platelets are unable to produce more cyclooxygenase and, therefore, the effect of aspirin will last until the platelet reaches the end of its lifespan and is replaced, generally in the region of seven to 10 days. Restoration of normal haemostasis does not seem to require all platelets to be replaced, and can be assumed five to seven days after stopping aspirin according to UK guidelines.1 It should be noted that cessation of aspirin is often not necessary prior to operative procedures – it carries a risk of thrombosis; specialist advice should be sought.

Thromboxane A2 production by cyclooxygenase is only one of numerous mechanisms of platelet activation, so while aspirin can be shown to reduce aggregation in response to a number of agonists in vitro, it does not abolish all platelet function.2

Antithrombotic doses used in clinical trials3 for the reduction of cardiovascular disease have varied widely from less than 50 mg to over 1,200 mg per day, with no evidence of any difference in clinical efficacy, although standard doses now vary between 75 and 300 mg daily. The major risk of aspirin treatment is that of gastrointestinal ulceration and haemorrhage.

Aspirin ‘resistance’

One subject which continues to receive much attention is the concept of so called aspirin ‘resistance’. This is defined in the laboratory as higher than expected platelet reactivity despite aspirin treatment. Causes are likely to be multifactorial and range from poor medication compliance, to genetic polymorphisms, to reduced platelet recovery time. There is some evidence that patients with responses to aspirin, which are lower than expected by laboratory testing, have a higher risk of cardiovascular events. However, there is, as yet, no consensus on which platelet function tests perform best in this setting and, perhaps more importantly, any indication of how the results of such testing should alter management.4 Certainly, increasing aspirin dose, or adding other antiplatelets, does not seem to alter outcomes.5 Tests for aspirin ‘resistance’ are therefore not yet routinely recommended outside the context of clinical trials.5

Aspirin in secondary prevention of cardiovascular disease

NICE recommends a dose of 75 mg aspirin daily as secondary prevention in all patients without a contraindication – a dose which is felt to provide the optimum balance between efficacy and gastrointestinal side effects.6

Aspirin in primary prevention of cardiovascular disease

The role of aspirin in primary prophylaxis against arterial thrombosis in those at risk is more controversial. Evidence for benefit is weak, and largely based on subgroup analyses of larger trials. On the whole, primary prophylaxis with aspirin is NOT recommended, as the small benefit is probably outweighed by the small risk of gastrointestinal bleeding. NICE guidance, drawing on position statements from the European Society for Cardiology (ESC), suggest considering primary prophylaxis only in the highest risk patients (hypertensive patients with renal impairment (eGFR <45 mls/min) and/or 10-year cardiovascular risk estimation of >20%)7. The POPADAD (Prevention of Progression of Arterial Disease and Diabetes) trial8 found no beneficial effect of aspirin in diabetic patients with asymptomatic peripheral artery disease.

Aspirin in atrial fibrillation

As discussed in module 1, thrombus formation in atrial fibrillation (AF) occurs under conditions of low shear and thus has more in common with venous thrombosis than arterial thrombosis. One might expect that aspirin would have limited efficacy in prevention of thrombosis and stroke in AF and, this does seem to be the case. Recent guidelines from NICE9 and the ESC10 do not recommend aspirin for stroke prevention in AF, as accumulating evidence suggests it is substantially less effective than anticoagulants at preventing stroke, while carrying a similar risk of bleeding.10 This will be discussed again in module 3.

Dipyridamole

Dipyridamole has a number of actions: as an inhibitor of phosphodiesterase it prevents the inactivation of cyclic adenosine monophosphate (cAMP). Hence, intra-platelet levels of cAMP are increased, resulting in reduced activation of second messengers within the cytoplasm. A second action is in the inhibition of thromboxane synthase, thus reducing platelet activation. A corollary of this is that more endoperoxides are available as a substrate for prostacyclin synthase, so that levels of prostacyclin rise, leading to vasodilation as well as platelet inhibition. Its effect is relatively short-lived and repeated dosing, or slow-release preparations are required in order to achieve 24-hour inhibition of platelet function.

Dipyridamole can be used along with aspirin in the secondary prevention of stroke and transient ischaemic attack, although recent NICE and Royal College of Physicians guidelines recommend clopidogrel monotherapy as the more cost-effective option, with aspirin plus dipyridamole reserved for patients with a contraindictation to clopidogrel.11,12

Side effects relate to its vasodilatory properties: gastrointestinal symptoms, dizziness, rash, tachycardia and worsening symptoms of coronary artery disease. Cautions include rapidly worsening angina, recent MI, heart failure, hypotension, and left ventricular outflow obstruction.

ADP-receptor blockage

ADP is a powerful stimulant of the platelet and acts via a specific purinoreceptor on the platelet surface. Release of ADP from dense granules is an important mechanism for positive feedback activation and recruitment of further platelets, so blockade of this pathway causes a reduction in platelet activity in response to a wide variety of stimuli. Ticlopidine, an earlier ADP inhibitor, is no longer used due to its haematological side effects. Three other drugs are currently available.

Clopidogrel

Clopidogrel is a thienopyridine derivative that is metabolised through cytochrome P450 in the liver. It dramatically inhibits platelet aggregation induced by the binding of ADP to its P2Y12 purinoreceptor on the platelet surface, a mechanism which appears to be independent of cyclooxygenase. The peak action on platelet function occurs after several days of oral dosing, and adverse effects include evidence of bone marrow suppression, in particular leucopenia.

Early trials of clopidogrel in cardiovascular disease, such as CAPRIE (Clopidogrel Versus Aspirin in Patients with Atherothombosis) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events),13,14 showed better outcomes in combination with aspirin compared with aspirin alone, a result widely confirmed in other settings (see figure 2). However, the CASPAR (Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Artery Disease) trial15 found no benefit of the addition of clopidogrel to aspirin in below-knee bypass grafting. Following the results of trials, such as the CURRENT–OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events − Seventh Organization to Assess Strategies in Ischemic Syndromes)16 this dual therapy is now recommended by NICE for post-acute coronary syndrome non-ST-elevation MI (NSTEMI) for 12 months, and post ST-elevation MI (STEMI) for at least four weeks after the infarction. A loading dose of 300–600 mg is generally followed by 75 mg daily.

Figure 2. Kaplan-Meier curves from the CURE study – the effect of long-term clopidogrel

A problem with clopidogrel follows from its prodrug status. It needs to be activated in the liver by cytochrome P450 enzymes, including CYP2C19. There are several isoforms of this enzyme: some confer loss of function (of which the most common is CYP2C19*2, possibly leading to clopidogrel resistance), while others (such as CYP2C19*17) cause a gain of function. Patients who carry one or two reduced function polymorphisms in this enzyme have been shown to be at risk of adverse cardiovascular outcomes, including stent thrombosis, leading to a Food and Drugs Administration (FDA) warning. However, a meta-analysis concluded that there is no consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel, and that the current evidence does not support the use of individualised antiplatelet regimens guided by CYP2C19 genotype.17 This may be because CYP2C19 genotype is only one of a number of factors which influence risk for further events in patients treated with clopidogrel.18

Another issue is that there is evidence that the use of proton-pump inhibitors (PPIs) (to reduce dyspepsia and gastrointestinal bleeding, which can be a significant problem in patients taking antiplatelet agents) reduces the antiplatelet effects of clopidogrel, most likely by inhibition of the CYP2C19 enzyme. Many local guidelines will thus advise avoidance of PPIs – especially omeprazole and esomeprazole – in patients taking clopidogrel. However, a recent meta-analysis concluded that the clinical impact of this interaction is probably not significant, pointing out that PPIs offer significant protection from gastrointestinal bleeding.19 Pending a definitive answer to this question, local policies should be followed.

Prasugrel

Prasugrel, like clopidogrel, is a thienopyridine prodrug that is metabolised partly in the plasma by an esterase and partly via the liver cytochrome P450 system to its active metabolite, which irreversibly inhibits the platelet P2Y12 receptor. The CYP2C19 enzyme appears to have a minor role in prasugrel metabolism and the drug’s onset of action is more rapid (within 30 minutes) and consistent than that of clopidogrel.20

Given this, one would expect that prasugrel would exert greater inhibition on platelet function that clopidogrel; this does seem to be the case, and this seems to be reflected in clinical outcomes, with fewer thrombotic events but more bleeding complications in patients on prasugrel. TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction)21 compared prasugrel and clopidogrel in over 13,000 patients, finding prasugrel to be associated with reduced cardiovascular death, non-fatal MI and stent thrombosis (HR 0.81), but more bleeding (HR 1.32). As the number of bleeds was smaller than the number of ischaemic events, there was felt to be an overall clinical benefit, although no significant mortality benefit was demonstrated.

By contrast, a second major trial, the phase III TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) study compared the effect of prasugrel (10 mg daily, or 5 mg daily in patients >75 years) with that of clopidogrel (75 mg daily)22 Over 7,000 acute coronary syndrome patients under 75 years with unstable angina or NSTEMI, managed without revascularisation and taking aspirin, were followed for up to 30 months. The primary end point of the trial was cardiovascular death, MI or stroke. The study was performed at 966 sites in 52 countries.

Results showed that, through a median follow-up period of 17 months, the primary end point occurred in 13.9% of those treated with prasugrel and 16.0% of those treated with clopidogrel (hazard ratio 0.91; 95% confidence interval [CI] 0.79–1.05; p=0.21). Thus, the first trial to study the effect of platelet inhibition in patients with acute coronary syndrome managed medically without revascularisation found no significant difference between prasugrel and clopidogrel in the prevention of death, MI or stroke. However, the pre-specified analysis of multiple recurrent ischaemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio 0.85; 95% CI 0.72–1.00; p=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups.

Ticagrelor

Figure 3. Processing of ADP-receptor blockers. Ticagrelor is absorbed as an active drug and binds reversibly to the ADP receptor. Prasugrel is part-metabolised by a plasma esterase and partly by hepatic cytochrome enzymes. Clopidogrel also needs to be modified by passage through the liver. Both prasugrel and clopidogrel bind irreversibly to the receptor

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine and is a direct and reversible P2Y12 antagonist, with a short half-life that requires twice-daily dosing, generally with a 90 mg tablet. Unlike clopidogrel and prasugrel, it is not a prodrug but acts directly and rapidly. The PLATO (Platelet Inhibition and Patient Outcomes) trial23 compared ticagrelor with clopidogrel in patients with STEMI, or moderate to high risk NSTEMI. Ticagrelor reduced the risk of a composite outcome of death from vascular causes, MI, or stroke (HR 0.84). There was no significant increase in major bleeding rates with ticagrelor overall, but there was a small increase in the risk of non-procedure related bleeding, including intracranial haemorrhage.

Apart from bleeding, side effects associated with ticagrelor include elevated creatinine concentrations, increased ventricular pauses, and dyspnoea (11.8% in PLATO study).

Cangrelor

Cangrelor is an intravenous ATP analogue, which provides reversible P2Y12 inhibition with rapid onset and offset (within one to two hours) of action. A recent meta-analysis of the three CHAMPION trials of cangrelor initiated at the beginning of percutaneous coronary intervention (PCI) versus clopidogrel, showed a 19% relative risk reduction in the primary end point of periprocedural death, MI, ischaemia-driven revascularisation and stent thrombosis, with a small increase in bleeding.24 It received marketing authorisation in the EU in 2015.

The differences in the metabolism of the three oral ADP-receptor blockers are summarised in figure 3.

Choosing an ADP-receptor blocker: a role for platelet function testing?

Prasugrel and ticagrelor both seem more effective than clopidogrel at preventing cardiovascular events but at a cost of increased bleeding risk. They are also considerably more expensive than clopidogrel, which is now off patent. Are there any laboratory tests which help us to decide which agent to prescribe for an individual patient?

We have seen that testing for CYP2C19 status has not yet gained universal acceptance as helpful in this context. Another approach has been to measure the reactivity of platelets following antiplatelet administration, with a view to switching therapy for those patients whose platelets do not seem adequately suppressed.

Platelet reactivity tests

Reference 25 has a detailed account of these tests and their clinical application.

VerifyNow® P2Y12 Assay (Accumetrics, USA)

This is perhaps the most widely used assay; it is quick and simple to use, and its small size makes it suitable for bedside testing. Whole blood is dispensed into a test cartridge containing ADP and fibrinogen-coated beads. Activated platelets aggregate and agglutinate on these beads, and this process is measured by light transmission through the sample. Light transmittance units are then converted into P2Y12 reaction units (PRUs). A consensus definition of high on-treatment platelet reactivity is a PRU >208.

Multiple electrode aggregometry (Multiplate, Roche Diagnostics, Switzerland)

This is a laboratory aggregometer, which measures platelet aggregation in whole blood by electrical impedance. It is only partially automated, therefore requiring the availability of trained laboratory staff.

Flow cytometric analysis of VASP phosphorylation

Vasodilator stimulated phosphoprotein (VASP) is a second messenger in the signalling pathway from the P2Y12 receptor. Stimulation of this receptor leads to dephosphoryation of VASP and this can be measured by flow cytometry. This measurement is highly specific for the P2Y12 pathway but is a technically difficult test requiring highly skilled staff.

There is accumulating evidence that high on-treatment platelet reactivity, as measured by these tests, is associated with adverse cardiovascular outcomes – at least for patients with acute coronary syndrome undergoing PCI. There is, however, not yet any good trial evidence that switching therapy based on the results of testing improves outcomes.18

In medically managed patients, and chronic ischaemic heart disease, there is not even any good evidence that platelet function testing adds any prognostic information above that provided by conventional risk factor assessment. In the TRILOGY ACS study, for example, high platelet reactivity by VerifyNow® was not an independent predictor of adverse events.18 The TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy with Prasugrel) trial enrolled 423 patients undergoing elective PCI with drug-eluting stent placement. All had platelet reactivity measured following clopidogrel administration; patients with an inadequate response were randomised to prasugrel or to continued clopidogrel. Although prasugrel was demonstrably more effective than clopidogrel at reducing platelet reactivity in these patients, this did not translate into statistically different outcomes. The event rate was, however, very low in both arms, limiting the usefulness of this study.26

Some smaller and non-randomised studies have reported data supporting a benefit for treatment changes based on platelet function tests, particularly in high-risk patients.18 Moreover, low on treatment platelet reactivity may be associated with increased bleeding risk and could be used to plan surgery in patients taking antiplatelet agents.18 The role of these tests may therefore increase in the future.

ADP receptor blockers – current guidelines

In the absence of agreement on the place of platelet testing, guidelines on ADP-receptor blocker choice are largely based on the available trial evidence.

NICE guidance on prasugrel (TA18227) is based on a detailed analysis of the TRITON-TIMI trial. Prasugrel is recommended as an option, in addition to aspirin, in acute coronary syndromes requiring PCI, only when: (i) immediate PCI for STEMI is required; or (ii) there is stent thrombosis in patients on clopidogrel; or (iii) in patients with diabetes.

For ticagrelor, NICE guidance (TA23628) recommends its use for up to 12 months, alongside low-dose aspirin, after an acute coronary syndrome (STEMI plus primary PCI, NSTEMI, or admission with unstable angina).

Recent ESC Guidelines recommend ticagrelor or prasugrel first line along with aspirin in patients with STEMI. For NSTEMI, ticagrelor is recommended for all patients at moderate to high risk of ischaemic events, with prasugrel as an option for those undergoing PCI. Clopidogrel is relegated to second line, for patients who can not receive either of the other agents, or who also require oral anticoagulation (where the bleeding risk with prasugrel or ticagrelor is felt to be unacceptably high).29,30

Clearly this has significant cost implications – local guidelines should be followed.

Preventing platelet–platelet interactions

GpIIb/IIIa, also known as integrin αIIbβ3 is the most important platelet surface receptor in achieving stable platelet aggregation. It binds fibrinogen, and other platelets via fibrinogen. It is the most abundant glycoprotein on the platelet surface, and its numbers and adhesive properties are increased by platelet activation of any cause (inside-out signalling). Binding to GpIIb/IIIa also contributes to platelet activation (outside-in signalling). The central importance of GpIIb/IIIa to platelet function is demonstrated by the severe bleeding phenotype associated with its congenital absence (Glanzmann’s thrombasthenia).

For all these reasons GpIIb/IIIa is an attractive target for critical occasions when profound platelet inhibition is required.Three GpIIb/IIIa inhibiting agents are available, each of which must be given by injection or infusion. They are NICE approved for the early management of high-risk patients with acute coronary syndromes for whom early PCI is planned; their use should be by specialists only.31

Abciximab

Abciximab has a long history, being first in its class, not only in GpIIa/IIIb blockage but also as a therapeutic monoclonal antibody. It is an established agent in the prevention of aggregation in acute coronary settings (alongside heparin and aspirin) and inhibits aggregation by 90% within two hours of its infusion. Platelet function then recovers over the course of two days but it has a major adverse effect of haemorrhage. There should be caution in its use in severe renal impairment. Abciximab can cause thrombocytopaenia within two to four hours of commencement. This can rarely be severe (<20 x 109/L).

Eptifibatide

Eptifibatide is a cyclic heptapeptide that mimics the part of the structure of fibrinogen that interacts with GpIIb/IIIa. Thus, it is a fraction of the size of abciximab and is targeted at the same structure on the platelet surface. It is licensed for the prevention of early MI in patients with unstable angina or NSTEMI. There is again caution in renal impairment, with a reduction in dose if estimated glomerular filtration rate (eGFR) <50 ml/min/1.73 m2, and should be avoided if eGFR <30 ml/min/1.73 m2.

Tirofiban

The third agent, tirofiban has a similar licence and contraindications as eptifibatide, including abnormal bleeding, severe hypertension (as this is a risk factor for haemorrhagic stroke), use of oral anticoagulants and hepatic impairment. However, the level of caution in renal disease is eGFR <60 ml/min/1.73 m2, with the use of half the dose when eGFR <30 ml/min/1.73 m2.

Other agents

Vorapaxar

Vorapaxar is a first in class oral inhibitor of the platelet thrombin receptor PAR-1. Its place in therapy is currently uncertain as trials to date have showed modest benefits in reducing ischaemic events, with substantial risks of haemorrhage, especially intracranial haemorrhage.29

Figure 4. Mode of action of receptor blockers. Targets of antithrombotic therapy include ADP and GpIIb/IIIa receptors. Blockage of these receptors prevents the activation of the second messengers crucial for initiation of thrombosis

Iloprost

Iloprost is a prostacyclin analogue that exerts its effects by promoting vasodilatation and inhibiting ADP-induced platelet aggregation, thereby opposing the effects of thromboxane A2. It may also increase the rate of metabolism of tissue plasminogen activator by the liver, but must be continuously infused.

Cilostazol

Cilostazol, like dipyridamole, is a phosphodiesterase inhibitor and so reduces platelet aggregation but also increases arterial vasodilation. Its use is restricted to those with intermittent claudication, in peripheral arterial disease patients.

Summary

Established antiplatelet agents are summarised in table 1, while figure 4 illustrates how our knowledge of platelet physiology has enabled us to inhibit its activity.

Table 1. Mechanism for suppressing platelet function

Haemorrhage

The British Committee for Standards in Haematology (BCSH) issued recent guidelines on the management of bleeding in patients taking antithrombotic agents.1 Simply stopping the agent may not be sufficient if bleeding is severe, as it may take several days for platelet function to return to normal (see table 2).

Table 2. Times to normal platelet function after cessation of antiplatelet agents

Options to stop bleeding range from basic haemostatic measures (pressure, surgical opinion) to platelet transfusion. Decisions regarding stopping/reversing antithrombotic agents have clear implications for thrombotic risk; specialist advice should be sought.

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References

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2. Harrison P, Mackie I, Mumford A et al. and British Committee for Standards in Haematology. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol 2011;155: 30–44. http://dx.doi.org/10.1111/j.1365-2141.2011.08793.x

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14. Mehta SR, Yusuf S, Peters RJ, et al. for the clopidogrel in unstable angina to prevent recurrent events trial (CURE) investigators. Effects of pre treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. http://dx.doi.org/10.1016/S0140-6736(01)05701-4

15. Belch JJ, Dormandy J; CASPAR writing committee. Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. J Vasc Surg 2010;52:825–33. http://dx.doi.org/10.1016/j.jvs.2010.04.027

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18. Tantry U, Bonello L, Aradi D et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013;62:2261–73. http://dx.doi.org/10.1016/j.jacc.2013.07.101

19. Cardoso RN, Benjo AM, DiNicolantonio JJ et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis. Open Heart 2015;2(1):e000248. http://dx.doi.org/10.1136/openhrt-2015-000248

20. Saboureta P, Taiel-Sartral M. New antiplatelet agents in the treatment of acute coronary syndromes. Arch Cardiovasc Dis 2014:107:178–87. http://dx.doi.org/10.1016/j.acvd.2014.01.009

21. Wiviott SD, Braunwald E, McCabe CH, et al. for the TRITON-TIMI 38 investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. http://dx.doi.org/10.1056/NEJMoa0706482

22. Roe MT, Armstrong PW, Fox KA, et al. for the TRILOGY ACS investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367:1297–309. http://dx.doi.org/10.1056/NEJMoa1205512

23. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. http://dx.doi.org/10.1056/NEJMoa0904327

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26. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012;59:2159–64. http://dx.doi.org/10.1016/j.jacc.2012.02.026

27. National Institute for Health and Care Excellence. Technology appraisal guidance TA182. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. London: NICE, October 2009. http://guidance.nice.org.uk/TA182/Guidance/pdf/English

28. National Institute for Health and Care Excellence. Technology appraisal guidance TA236. Ticagrelor for the treatment of acute coronary syndromes. London: NICE, October 2011. http://www.nice.org.uk/ta236

29. Roffi M, Patrono C, Collet J, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2015;pii: [Epub ahead of print]. http://dx.doi.org/10.1093/eurheartj/ehv320

30. Steg PG, James SK, Atar D et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012;33:2569–619. http://dx.doi.org/10.1093/eurheartj/ehs215

31. National Institute of Health and Care Excellence. CG94. Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. London: NICE, 2010 (accessed 13.9.2015).

Further reading

Sharma RK, Voelker DJ, Sharma R, Reddy HK, Dod H, Marsh JD. Evolving role of platelet function testing in coronary artery interventions. Vasc Health Risk Manag 2012;8:65–75. http://dx.doi.org/10.2147/VHRM.S28090

Michelson AD. Advances in antiplatelet therapy. Hematology Am Soc Hematol Educ Program 2011;2011:62–9. http://dx.doi.org/10.1182/asheducation-2011.1.62

Gasparyan AY. Aspirin and clopidogrel resistance: methodological challenges and opportunities. Vasc Health Risk Manag 2010;6:109–12. http://dx.doi.org/10.2147/VHRM.S9087

National Institute for Health and Clinical Excellence. CG48. Secondary prevention in primary and secondary care for patients following a myocardial infarction. London: NICE, May 2007. Available from: http://guidance.nice.org.uk/CG48

Breet NJ, van Werkum JW, Bouman HJ et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010;303:754–62. Erratum in: JAMA 2010;303:1257. http://dx.doi.org/10.1001/jama.2010.181

Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart 2016;3:e000279. http://dx.doi.org/10.1136/openhrt-2015-000279

See also www.bnf.org

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