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.
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.
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).
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.
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 (https://cks.nice.org.uk/antiplatelet-treatment#!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 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.
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
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.
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 (https://cks.nice.org.uk/antiplatelet-treatment#!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.
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
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
|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
|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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