Anticoagulation module 2: Antiplatelet therapy

Released 27 October 2021     Expires: 27 October 2023      Programme:

Sponsorship Statement:

This latest 2021 revision and earlier revisions of the anticoagulation modular programme have been funded by educational grants from Bayer. Bayer had no role in the writing of the modules and had no editorial control over the content.

The programme was originally supported by an educational grant from Bristol Myers Squibb (BMS) and Pfizer. BMS and Pfizer had no role in the writing of the modules and had no editorial control over the content.


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 to the British Heart Foundation,1 annually in the UK there are over 100,000 hospital admissions due to myocardial infarction (MI), and over 100,000 due to strokes. There are around 1.4 million people living in the UK who have survived a heart attack, and around 1.3 million survivors of stroke or transient ischaemic attack (TIA). Coronary heart disease was the second leading cause of UK deaths in 2019, and stroke was the fifth. About 20% of the UK population aged over 60 years have some degree of 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 passively crosses the membrane and irreversibly inhibits cyclooxygenase (COX) by acetylation of the amino acids adjacent to the active site. The COX enzyme performs the rate-limiting step in synthesis of thromboxane A2 (TXA2) from arachidonic acid (see figure 1).

Figure 1. Key elements of platelet function, showing current pharmacological targets
Figure 1. Key elements of platelet function, showing current pharmacological targets

Without a nucleus, platelets are unable to produce more COX 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.2 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.

TXA2 production by COX 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.3

Antithrombotic doses used in clinical trials4 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, it may be appropriate to prescribe a proton pump inhibitor to reduce this risk.

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.5 Certainly, increasing aspirin dose, or adding other antiplatelets, does not seem to alter outcomes.6 Tests for aspirin ‘resistance’, for example by Multiplate (see below) are therefore not yet routinely recommended outside the context of clinical trials.6

Aspirin in secondary prevention of cardiovascular disease

The National Insititute of Health and Care Excellence (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.7

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. In these patients it is suggested to use non-pharmacological measures to reduce their cardiovascular disease risk such as stopping smoking. NICE guidance, drawing on position statements from the European Society for Cardiology (ESC), suggest considering primary prophylaxis only in the highest risk patients (10-year cardiovascular risk estimation of >20%).8

In patients with asymptomatic lower extremity arterial disease, the ESC9 recommends that aspirin is not indicated, based on two trials showing no significant benefit, one in a general population with an ankle brachial index (ABI) <0.95, and the other in patients with diabetes in the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) trial10. Conversely, it does recommend long-term aspirin therapy in patients with a carotid artery stenosis >50%, irrespective of clinical symptoms.

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 NICE11 and the ESC12 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.12

In the event of a patient refusing warfarin or a direct oral anticoagulant (DOAC) for stroke prevention in AF, then antiplatelet agents may be considered. Clopidogrel is licensed for use in combination with aspirin for people with AF in whom anticoagulants are unsuitable (!scenario:1).

This will be discussed again in module 3.


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 national stroke guidelines recommend clopidogrel monotherapy as the more cost-effective option, with aspirin plus dipyridamole reserved for patients with a contraindication to clopidogrel.13,14

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 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 such as leucopenia, although this is rare.

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),15,16 showed better outcomes in combination with aspirin compared with aspirin alone, a result widely confirmed in other settings (see figure 2). 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),17 this dual therapy was approved for secondary prevention following acute coronary syndrome (ACS), with or without ST-elevation, in patients being medically managed and those undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting.18 Over recent years, there has been a switch away from clopidogrel for first-line use in dual antiplatelet therapy (DAPT) with aspirin, in favour of more potent drugs such as ticagrelor and prasugrel.1) (see section below ‘ADP receptor blockers – current guidelines’). Clopidogrel monotherapy is the antiplatelet of choice in the secondary prevention of stroke/TIA, and peripheral artery disease.

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.20 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.21

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 2015 meta-analysis concluded that the clinical impact of this interaction is probably not significant, pointing out that PPIs offer significant protection from gastrointestinal bleeding.22 Pending a definitive answer to this question, local policies should be followed.


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.23

Given this, one would expect that prasugrel would exert greater inhibition on platelet function than 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)24 compared prasugrel and clopidogrel in over 13,000 patients, including ACS patients in whom coronary anatomy was deemed suitable for PCI, and patients with ST-segment elevation myocardial infarction (STEMI) referred for primary PCI. It found that prasugrel was associated with a reduction in the composite end point of cardiovascular death, non-fatal MI and stent thrombosis (HR 0.81), mostly driven by a 24% relative risk reduction for MI. Prasugrel was, however, associated with 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.

One should note that prasugrel is only approved for ACS patients in whom coronary anatomy has been assessed and deemed suitable for PCI, with the exception of STEMI patients referred for primary PCI. This is based on the ACCOAST (Comparison of Prasugrel at the Time of PCI or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction) randomised control trial,25 which showed that among patients with non-ST elevation ACS (NSTEMI) who were scheduled to undergo coronary angiography, pretreatment with prasugrel did not reduce the rate of major ischaemic events up to 30 days but did increase the rate of major bleeding complications.

The role of prasugrel in medically managed ACS patients was addressed by the phase III TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) study, which compared the effect of prasugrel (10 mg daily, or 5 mg daily in patients >75 years) with that of clopidogrel (75 mg daily)26 Over 7,000 ACS 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 ACS managed medically without revascularisation found no significant difference between prasugrel and clopidogrel in the prevention of death, MI or stroke. Rates of severe and intracranial bleeding were similar in the two groups in all age groups. Prasugrel is therefore not licensed or approved for ACS patients undergoing medical management alone.


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) trial27 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).

A head-to-head comparison between ticagrelor- and prasugrel-based DAPT treatment strategies was undertaken by the ISAR-REACT 5 (The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment ) trial,28 which randomised 4,018 ACS patients, with or without ST- elevation, who were scheduled to undergo coronary angiography. It found that prasugrel was superior to ticagrelor with respect to the composite end point of death, MI, or stroke at one year, primarily driven by fewer MIs in the prasugrel group, without a significant difference in major bleeding rates. The results of this trial were influential for the recent NICE recommendation favouring prasugrel over ticagrelor in STEMI patients undergoing PCI.29


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

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 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.30 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 31 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.

Figure 4 shows a multiple analyser along with typical tracings. (Image taken from the Multiplate website

Anticoagulation Module 2 multiplate-p
Figure 4. A multiple analyser showing typical tracings obtained

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, a lack of high quality trial evidence that escalating therapy based on the results of testing improves outcomes.21

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.32

Moreover, the GRAVITAS (Gauging Responsiveness With a VerifyNow Assay—Impact on Thrombosis and Safety) trial randomised 2,214 post-PCI patients with high on-treatment platelet reactivity, and showed no advantage from escalation to high-dose clopidogrel over standard dose.33

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.21

In more recent times – with improvements in post-ACS ischaemic risk resulting from advances in drug-eluting stent technology and use of more potent ADP receptor blockers – the potential for early de-escalation of DAPT guided by platelet reactivity tests has received interest, particularly as a means of reducing bleeding risk. The TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes) trial34 randomised post-PCI ACS patients to either standard DAPT therapy with 12 months of prasugrel, or early de-escalation from day 14 guided by platelet function testing. Patients in the de-escalation group found to have high platelet reactivity on clopidogrel were switched back to prasugrel. The trial met its primary end point by demonstrating noninferiority of guided de-escalation, with similar rates of ischaemic events (cardiovascular death, MI, or stroke) and a trend toward less bleeding.

As things stand, ESC practice guidelines35, along with a updated expert consensus statement,36 recommend that platelet reactivity tests should not be used routinely to tailor DAPT but may be considered in specific clinical scenarios.

Another potential application of platelet reactivity testing could be to guide timing of surgery in patients taking antiplatelet agents, by using reactivity data to help estimate bleeding risk.

The role of these tests may 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 (!scenario:1).

In ACS that is to be medically managed, DAPT is required – usually aspirin with ticagrelor for at least 12 months, unless the bleeding risk is too high, in which case clopidogrel is favoured.

For people with acute STEMI who are undergoing PCI, aspirin should be used in combination with prasugrel 10 mg daily (or 5 mg daily in patients <60 kg or aged ≥75 years). Ticagrelor (90 mg twice daily) or clopidogrel (75 mg daily) are alternative options for patients aged ≥75 years in whom the bleeding risk of prasugrel is felt to exceed the therapeutic benefit.

For people with unstable angina or NSTEMI undergoing PCI, aspirin should be used in combination with either prasugrel or ticagrelor unless bleeding risk is considered excessive, in which case clopidogrel can be used an alternative ADP receptor blocker.

In patients with stable coronary artery disease who are due to undergo PCI, the preferred treatment option is aspirin with clopidogrel (although ticagrelor or prasugrel can be used instead of clopidogrel where appropriate).

When using DAPT, the bleeding risk must be taken into account when considering duration of use.

In ACS patients with a separate ongoing indication for oral anticoagulation therapy, the NICE guidance carries a consensus recommendation that DAPT should be converted to single antiplatelet therapy after the initial treatment phase (undefined in duration), due to increased bleeding risk. For patients who have had PCI and stenting, the oral anticoagulant should be combined with clopidogrel, whereas for those who have not had stenting, it should be combined with aspirin. Generally, ticagrelor and prasugrel should be avoided in this setting. A recommendation on choice of oral anticoagulant is not made.

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. There have been three GpIIb/IIIa inhibitors available for clinical use, one of which – abciximab – went out of production in 2019.

Their use should be by specialists only.


Abciximab has a long history, being first in its class, not only in GpIIa/IIIb blockage but also as a therapeutic monoclonal antibody. It was 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). Platelet count typically recovers after stopping the drug.


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. 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.


The third agent, tirofiban has similar contraindications to 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.

Eptifibatide (in combination with unfractionated heparin and aspirin) and tirofiban (in combination with unfractionated heparin, aspirin, and clopidogrel) are licensed for use to prevent early MI in patients with unstable angina or NSTEMI. Tirofiban is also licensed for use in combination with unfractionated heparin, aspirin, and clopidogrel, for the reduction of major cardiovascular events in patients with STEMI intended for primary percutaneous coronary intervention.

However, in the setting of potent antiplatelet treatment with prasugrel and ticagrelor, their role is less well defined, and recent ESC35 and NICE29 guidelines limit their use largely to high risk ‘bail-out’ situations.

Other agents


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.37


Figure 5. 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 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, 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.


Established antiplatelet agents are summarised in table 1, while figure 5 illustrates how our knowledge of platelet physiology has enabled us to inhibit its activity.

Table 1. Mechanism for suppressing platelet function

Mechanism Route of administration Examples of agents
Inhibition of metabolic pathways Oral Aspirin
GpIIb/IIIa blockade Injection/infusion Abciximab
ADP-receptor blockade Oral Clopidogrel
ADP-receptor blockade intravenous Injection/infusion Cangrelor
Key: ADP = adenosine diphosphate; Gp = glycoprotein


The British Committee for Standards in Haematology (BCSH) issued guidelines on the management of bleeding in patients taking antithrombotic agents.2 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

Aspirin 5–7 days
Clopidogrel 5–7 days
Prasugrel 5–7 days
Ticagrelor 3–5 days
Tirofiban 4–8 hours
Eptifibatide 4–8 hours
Abciximab 24–48 hours
Dipyridamole 24 hours
Adapted from Makris2

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.

A further BCSH guideline38 makes recommendations for perioperative management of antiplatelet therapy, including cardiovascular, non-cardiac and emergency surgery.

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1. British Heart Foundation. BHF Statistics Factsheet – UK. March 2021. [last accessed 11th May 2021]

2. Makris M, Van Veen J J, Tait C R, Mumford A D, Laffan M. Guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol 2013:160:35–46.

3. 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.

4. Antiplatelet trialists collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106. Erratum in: BMJ 1994;308:1540.

5. Dretzke J, Riley R, Lordkipanidzé M et al. The prognostic utility of tests of platelet function for the detection of ‘aspirin resistance’ in patients with established cardiovascular or cerebrovascular disease: a systematic review and economic evaluation. Health Technol Assess 2015;19:1–366.

6. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008;336:195–8.

7. National Institute for Health and Care Excellence. Myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease. Clinical guideline [CG172]. London: NICE, 2013. [last accessed 11th May 2021]

8. National Institute for Health and Care Excellence. Clinical Knowledge Summaries: antiplatelet treatment. London: NICE, last revised August 2020. [last accessed 11th May 2021]

9. Aboyans V, Ricco J, Bartelink M, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Eur Heart J 2018; 39:763-816.

10. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840.

11. National Institute for Health and Care Excellence. Atrial fibrillation: diagnosis and management. Clinical guideline [NG196]. London: NICE 2021. [last accessed 11th May 2021]

12. Hindricks G, Potpara T, Dagres N et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373–498

13. National Institute for Health and Care Excellence. Technology appraisal guidance [TA210]. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. London: NICE, 2010. [last accessed 11th May 2021].

14. Royal College of Physicians. National clinical guideline for Stroke (Fifth Edition), prepared by the Intercollegiate Stroke Working Party. London: Royal College of Physicians, 2016. [last accessed 11th May 2021]

15. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–39.

16. 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.

17. Mehta SR, Tanguay JF, Eikelboom JW et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376:1233–43.

18. Valgimigli M, Bueno H, Byrne RA et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur J Cardiothorac Surg. 2017;53:34–78.

19. Chan NC, Weitz JI. Antiplatelet therapy in the management of atherothrombosis: recent clinical advances. Blood Adv. 2018;2:1806.

20. Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 2011;343:d4588.

21. 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.

22. 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.

23. Saboureta P, Taiel-Sartral M. New antiplatelet agents in the treatment of acute coronary syndromes. Arch Cardiovasc Dis 2014:107:178–87.

24. 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.

25. Montalescot G, Bolognese L, Dudek D, et al., for the ACCOAST Investigators. Pretreatment with Prasugrel in Non–ST-Segment Elevation Acute Coronary Syndromes. N Engl J Med 2013;369:999-1010

26. 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.

27. 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.

28. Schüpke S, Neumann F, Menichelli M, et al., for the ISAR-REACT 5 Trial Investigators. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med 2019;381:1524-1534

29. National Institute for Health and Care Excellence. Acute coronary syndrome. NICE guideline [NG185]. London: NICE 2020. [last accessed 11th May 2021]

30. Steg P, Bhatt D, Hamm C, et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 2013;382:1981–92.

31. Aradi D, Storey R, Komócsi A, et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 2014;35:209–15.

32. 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.

33. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305(11):1097–105.

34. Sibbing D, Aradi D, Jacobshagen C, et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017;390:1747–57.

35. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165.

36. Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019;12:1521–37.

37. 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. Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2015;37:267–315.

38. Keeling D, Campbell Tait R, Watson H. Perioperative management of anticoagulation and antiplatelet therapy. Br J Haematol 2016:175:602–13.

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.

Michelson AD. Advances in antiplatelet therapy. Hematology Am Soc Hematol Educ Program 2011;2011:62–9.

Gasparyan AY. Aspirin and clopidogrel resistance: methodological challenges and opportunities. Vasc Health Risk Manag 2010;6:109–12.

National Institute for Health and Care Excellence. Secondary prevention in primary and secondary care for patients following a myocardial infarction. CG84. London: NICE, May 2007. Available from:

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,/i> 2010;303:1257.

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.

See also

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All rights reserved. No part of this programme may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publishers, Medinews (Cardiology) Limited.

It shall not, by way of trade or otherwise, be lent, re-sold, hired or otherwise circulated without the publisher’s prior consent.

Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment and the use of drugs becomes necessary. The editors/authors/contributors and the publishers have taken care to ensure that the information given in this text is accurate and up to date. Readers are strongly advised to confirm that the information, especially with regard to drug usage, complies with the latest legislation and standards of practice.

Healthcare professionals should consult up-to-date Prescribing Information and the full Summary of Product Characteristics available from the manufacturers before prescribing any product. Medinews (Cardiology) Limited cannot accept responsibility for any errors in prescribing which may occur.