Antiplatelet therapy in cardiovascular disease: Current status and future directions

Antiplatelet medications remain a cornerstone of therapy for atherosclerotic cardiovascular and cerebrovascular diseases. In primary prevention (patients with cardiovascular risk factors but no documented events, symptoms or angiographic disease), there is little evidence of benefit of any antiplatelet therapy, and such therapy carries the risk of excess bleeding. Where there is documented disease (secondary prevention), stable patients benefit from long‐term antiplatelet monotherapy, aspirin being first choice in those with coronary heart disease and clopidogrel in those with cerebrovascular disease; moreover, recent evidence shows that low‐dose rivaroxaban in combination with aspirin confers added benefit, in patients with stable cardiovascular and peripheral arterial disease. In patients with acute cerebrovascular disease, aspirin combined with clopidogrel reduces subsequent risk, while in acute coronary syndrome, dual antiplatelet therapy comprising aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) confers greater protection than aspirin monotherapy, with prasugrel and ticagrelor offering greater antiplatelet efficacy with faster onset of action than clopidogrel. Although greater antiplatelet efficacy is advantageous in preventing thrombotic events, this must be tempered by increased risk of bleeding, which may be a particular issue in certain patient groups, as will be discussed. We will also discuss possible future approaches to personalisation of antiplatelet therapy.


| INTRODUCTION
The cyclooxygenase (COX) inhibitor aspirin was first introduced into cardiovascular prophylaxis in the 1980s, and the subsequent introduction of the adenosine purinergic (ADP) receptor P2Y 12 inhibitors not only offered an alternative for aspirin-intolerant patients, but also the potential for high intensity platelet inhibition due to simultaneous blockade of COX and ADP-dependent pathways. However, the more potent antithrombotic action from blockade of both pathways also carries a higher risk of bleeding complications; and although concomitant proton-pump inhibitor therapy will help to prevent gastrointestinal haemorrhage in patients with acid peptic disease, it will not abolish the risk, nor will it impact bleeding at other sites.
Much research has therefore centred around the appropriate use of dual antiplatelet therapy (DAPT) to establish both optimal drug combination and ideal duration of treatment, aiming for a net positive balance between beneficial (antithrombotic) and detrimental (bleeding) effects.
Here we aim to clarify for clinicians the evidence for the use of aspirin and P2Y 12 inhibitors in different clinical situations, either as mono or dual therapy. We will also touch on the place of anticoagulation on top of antiplatelet therapy in the context of atherosclerotic diseases. Finally, we will consider whether personalised approaches to antiplatelet therapy may be useful for maximising benefit/risk ratio.

| KEY PHARMACOLOGY
The principal agents in clinical use are aspirin (acetylsalicylic acid) and the P2Y 12 receptor inhibitor drugs clopidogrel, prasugrel and ticagrelor ( Figure 1).
Aspirin acetylates a critical serine residue in the active site of the COX-1 isoenzyme, causing irreversible inhibition of platelet COX activity with consequent suppression of thromboxane-dependent platelet activation.
The P2Y 12 receptor on the platelet surface binds ADP, which, via the mediation of Gi protein, activates the platelet glycoprotein IIb/IIIa receptor resulting in enhanced platelet degranulation, thromboxane production and platelet aggregation. The first P2Y 12 inhibitor developed for clinical use, ticlopidine, a thienopyridine derivative, was rapidly replaced by the second-generation thienopyridine clopidogrel in view of its more favourable safety profile. 1 Subsequently, the third generation thienopyridine prasugrel was developed, which exhibited the advantages of increased efficacy and more predictable metabolism of prodrug to active drug. 2 Both clopidogrel and prasugrel require oxidation by hepatic cytochrome P450 to be converted to their active metabolites. The active molecules selectively and irreversibly bind P2Y 12 receptors on platelets, thus preventing ADP-dependent platelet activation. 3 Ticagrelor is a reversible P2Y 12 inhibitor of the cyclo-pentyltriazolo-pyrimidine class that, unlike the thienopyridines, is active in its own right and does not require hepatic metabolism to exert its pharmacological action, although cytochrome-mediated oxidation of the drug is extensive and leads to the formation of an active metabolite that also contributes to the therapeutic effect. 4 It therefore exhibits faster offset of effect. A common adverse event is dyspnoea which represents the most frequent cause of therapy discontinuation (physician-recommended drug cessation), interruption (temporary drug cessation) or disruption (unplanned cessation due to adverse events or lack of adherence). 5 As this review centres on antiplatelet therapy, we will not discuss the pharmacology of the direct oral anticoagulants (DOACs), which has been reviewed in detail recently. 6 Nevertheless, it is pertinent to mention the DOACs here, because of much recent interest in the concomitant use of DOACs with antiplatelets for cardiovascular prevention, largely thanks to the results of the COMPASS trial (Table 1), 12 which will be discussed below.
F I G U R E 1 Antiplatelet drug mechanisms of action. The thienopyridines clopidogrel and prasugrel prevent ADP from binding its specific P2Y 12 receptor and cause its irreversible inhibition; ticagrelor exerts reversible P2Y 12 receptor antagonism. While clopidogrel and prasugrel require hepatic metabolism to produce the active drug metabolite, ticagrelor is not a prodrug and has a direct inhibitory action, although additionally undergoing a cytochrome-dependent oxidation that also produces an active metabolite contributing to the pharmacological effect. Aspirin irreversibly blocks the enzymatic activity of cyclooxygenase-1 (COX-1), which is a key enzyme in the metabolism of arachidonic acid to produce prostanoids. COX-1 converts arachidonic acid to the unstable intermediate prostaglandin G2 (PGG2). Further metabolism of PGG2 by hydroperoxidases (HOX) leads to prostaglandin H2 synthesis that is finally converted into prostanoids by tissue-specific isomerases (platelets mainly contain thromboxane A2 [TxA2] synthase resulting in production and release of TxA2

| PRIMARY PREVENTION
Despite the now well-established role of aspirin in secondary cardiovascular prophylaxis, the benefit/risk ratio in primary prevention is far less clear. In low-and middle-income countries, aspirin-containing polypill strategies have proved effective in preventing major cardiovasacular events, for example in the PolyIran study. 24 However, a large meta-analysis conducted by the Antithrombotic Trialists' collaboration from 2009 questioned the net benefit of aspirin in primary prevention as a result of an observed increased risk of major extracranial and gastrointestinal bleeding complications in spite of only a small protective effect against vascular events. 25 These findings have been confirmed by the most recent trials conducted in primary prevention: for example, ASPREE, which focused on elderly subjects, ASCEND, which studied patients with diabetes, and ARRIVE, which examined patients with a moderate estimated risk of a first cardiovascular event, [26][27][28] showing that the net benefit of aspirin in this setting is marginal at best whilst posing a major bleeding hazard in subjects with cardiovascular risk factors who are otherwise healthy. At present, therefore, a cautious approach is advised as regards the use of aspirin in primary prevention, weighing the benefit to risk ratio in order to personalise treatment.

| SECONDARY PREVENTION: CORONARY ARTERY DISEASE
According to the most recent European guidelines, 29 CHA₂DS₂-VASc score). In patients with combined coronary disease and atrial fibrillation at low bleeding risk, combination antiplatelet and anticoagulant therapy may be considered, in which situation evidence supports the use of clopidogrel and a DOAC, rather than regimens that include a vitamin K antagonist, aspirin, or both, due to less bleeding and fewer hospitalisations without significant differences in the incidence of ischaemic events; this includes patients post-ACS or percutaneous coronary intervention (PCI). 31 The only available direct comparison of clopidogrel vs. aspirin in the context of CCS is provided by the CAPRIE study ( In the GLOBAL LEADERS trial (Table 1), 9 ticagrelor given in combination with aspirin for 1 month followed by 23 months of ticagrelor monotherapy failed its primary superiority outcome on safety compared to 12 months of standard DAPT followed by 12 months of aspirin alone. By contrast, the TWILIGHT-ACS study 10 (Table 1)    but not CHANCE reported a higher rate of major bleeding complications; and, in a secondary analysis, the benefit of DAPT was apparent predominantly during the first 21 days of therapy. 55 The recently published THALES trial (Table 2) showed that, among patients with a mild-to-moderate acute noncardioembolic ischaemic stroke or TIA who were not undergoing thrombolysis, the risk of the composite of stroke or death within 30 days was lower with combination ticagrelor and aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the 2 groups; severe bleeding was more frequent with ticagrelor. 54 Therefore, unlike the prophylaxis of cardiac events, secondary prevention of cerebral events by DAPT has shown advantage over monotherapy only in short-term therapy and for patients with minor stroke or TIA. This is probably due to the increased probability of reoccurrence of a major stroke, often disabling, within 2 weeks from the first event 56 ; the bleeding risk associated with antithrombotic therapies is generally early from therapy initiation, although it may decline after the first month. 57 For long-term prophylaxis, the combination of aspirin and dipyridamole can be considered as long as it is tolerated. Two major trials tested this combination, namely the ESPS2 47 and ESPRIT 48 studies (Table 2), demonstrating advantage in terms of a composite endpoint of death from all vascular causes, stroke and MI for aspirin plus dipyridamole over aspirin alone, without significant impact on haemorrhagic risk. However, a high therapy discontinuation rate (about 6%) 58 has been reported for this combination, which appears to be related to the occurrence of headache.
Where monotherapy is considered for long term prophylaxis, clopidogrel is preferred over aspirin on the basis of both the CAPRIE results, 7 comparing clopidogrel to aspirin, and the PRO-FESS trial, 43 testing clopidogrel against aspirin plus dipyridamole, which respectively reported greater protection with clopidogrel than with aspirin and similar protection to aspirin plus dipyridamole, against a composite of ischaemic stroke, myocardial infarction, or vascular death ( Table 2). These results were recently confirmed by a meta-analysis of 5 trials including CAPRIE. 59 Triple antiplatelet therapy of aspirin, clopidogrel and dipyridamole is not recommended in secondary prevention of stroke as it does not enhance protection but significantly increases the risk of major bleeding. 60 Hence, current guidelines suggest either clopidogrel or aspirin plus dipyridamole as equivalent alternatives for long-term secondary prophylaxis of stroke. NNT: number needed to treat for primary efficacy outcome (with 95% confidence intervals). Negative value indicates control treatment more efficacious on primary outcome than experimental treatment. NNH: number needed to harm for primary safety outcome (with 95% confidence intervals). Negative value indicates control treatment gives more harm than experimental treatment. Values for NNT and NNH are only given for clinical outcomes and if the difference in efficacy or harm attained statistical significance in the study. TIA, transient ischaemic attack.

| PERIPHERAL ARTERIAL DISEASE
There is no clear consensus between different international guidelines on antithrombotic therapy in stable PAD. Data in this situation largely derive from subanalyses of randomised trials of patients with various manifestations of atherosclerosis, including coronary disease, cerebrovascular disease and PAD. Currently there is no convincing evidence for efficacy of any antithrombotic strategy in patients with asymptomatic PAD whereas, by contrast, the evidence of benefit is much clearer in those with symptomatic PAD. Single antiplatelet therapy with either aspirin or clopidogrel is well established to reduce cardiovascular risk, and more recently data from the COMPASS trial support combined therapy with aspirin and rivaroxaban in this situation. 12 Patients who undergo either surgical or endovascular revascularisation for PAD should be prescribed lifelong antithrombotic therapy; and dual antithrombotic therapy with aspirin plus rivaroxaban is recommended, on the basis of the recently published VOYAGER PAD trial (Table 1), 14 which demonstrated that addition of rivaroxaban 2.5 mg twice a day to aspirin in such patients reduced the relative incidence of the composite outcome of acute limb ischaemia, amputation for vascular causes, MI, ischaemic stroke or cardiovascular death by 15%, with no significant increase in TIMI major bleeding, compared to aspirin alone.

| Kidney disease
Kidney disease is considered a coronary heart disease risk equivalent, and as such it carries a particularly high cardiovascular risk according to guidelines. 29,30 The use of antiplatelet drugs in patients with chronic kidney disease accordingly follows the recommendations that apply to patients in the very high cardiovascular risk category, even though evidence in support of therapy decision making is limited by a paucity of data, especially for patients with end-stage renal disease and those on dialysis who were often excluded from trials. Although some evidence had suggested an association between aspirin use and increased risk of MI in patients on haemodialysis, 61 and another observational study had reported increased mortality associated with antithrombotic treatment in patients with kidney disease, 62 despite lack of randomised controlled trial data, the weight of evidence suggests that antiplatelet treatment (used in accordance with current guidelines for patients at very high cardiovascular risk) is beneficial in patients with advanced kidney disease, the overall benefits outweighing the risks; but that a carefully tailored approach should be taken where the bleeding risk is judged to be especially high in an individual.
As discussed above, dual pathway inhibition with aspirin and rivaroxaban is now licensed for treatment of patients with CCS and PAD. However, since rivaroxaban (and indeed other DOACs) are predominantly excreted renally, the rivaroxaban plus aspirin combination should be used with caution in patients with kidney disease.

| Diabetes
Given the known increase in prothrombotic status conferred by diabetes, antiplatelet prophylaxis was widely used in patients with diabetes (both types 1 and 2) for primary prevention until evidence from the Antithrombotic Trialists' Collaboration Collaborative meta-analysis indicated lack of benefit of aspirin in the absence of established cardiovascular disease. Antiplatelet drugs are now prescribed, as in nondiabetics, in patients with prior cardiovascular events and/or established disease. 29,30 Of note, the benefit of DAPT post-PCI appeared to be more pronounced in diabetics than nondiabetics in TRITON-TIMI 38 (17 vs. 12.2% relative reduction of ischaemic events in the respective groups), based on which prasugrel is now indicated by guidelines for DAPT in diabetic patients post-PCI. 30 The THEMIS trial 63  Similarly, in cerebrovascular disease, the PRINCE trial (Table 2) showed that patients with minor stroke or TIA treated with ticagrelor plus aspirin exhibit reduced platelet reactivity compared to those receiving clopidogrel plus aspirin, especially so in carriers of the CYP2C19 LOF allele. 53 Whether this translates into improved clinical outcomes remains unknown.
At present, therefore, platelet function testing remains of uncertain usefulness for treatment decision making, although research continues to explore whether better definition of patient groups in whom such testing might be beneficial might improve its applicability. A frequent clinical concern is what to do as regards antiplatelet therapy (both its use and its intensity) in patients with a history of prior bleeding. The clinician's judgement in such situations should take into account the site and severity of that bleeding, as well as how long ago it happened, what the circumstances/precipitants were, and whether the underlying cause was adequately treated. As we have discussed throughout the article, the most important consideration for the clinician should be the risk of future, as opposed to simply a history of previous, bleeding.

| CONCLUSIONS
Genotyping and platelet function testing allow ever more accurate prediction of the effects of antiplatelet therapies on platelet function in vitro. At present, use of these has not been clearly demonstrated to translate into clinical utility, although further research is needed to clarify whether they may be of use in certain better defined patient populations.