Academic Editor: Peter A. McCullough
Platelets participate centrally in atherothrombosis, resulting in vessel
occlusion and ischaemia. Consequently, optimisation of antiplatelet regimens has
the potential to further reduce the residual burden of morbidity and mortality
associated with atherosclerosis. Ticagrelor is a potent oral platelet P2Y
The formation of atherosclerotic plaques increases the risk of arterial
thrombosis that can result in vascular occlusion and subsequently ischaemia or
infarction of the distal tissue. The most devastating conditions that manifest
clinically as a result of this process include cardiovascular death, myocardial
infarction (MI) and stroke, otherwise collectively known as major adverse
cardiovascular events (MACE), markedly contributing to the global burden of
premature morbidity and mortality [1]. In the coronary arteries, atherothrombosis
may present rapidly as an acute coronary syndrome (ACS), which includes
ST-elevation MI (STEMI) and non-ST-elevation ACS (NSTE-ACS). Subclinical
atherothrombosis may also contribute to the progression of atherosclerotic
disease in patients with chronic coronary syndromes (CCS), which includes
so-called stable coronary artery disease (CAD) or an ACS event more than 1 year
ago [2, 3, 4, 5, 6]. Platelets are central to this pathophysiological process and,
therefore, the development of antiplatelets aims to reduce the risk of MACE by
therapeutically antagonising various mechanisms involved in the activation and
aggregation of platelets [7]. The combined inhibition of thromboxane A
While contemporary advances have improved the control of modifiable risk
factors, reduced complications associated with percutaneous coronary intervention
(PCI) [8], and reduced the risk of recurrent ischaemia post-ACS, there remains a
significant degree of residual risk in patients with CAD. Ticagrelor provides
several hypothetical and pharmacological advantages over aspirin and other oral
P2Y
Visual abstract of randomised clinical trials and pre-specified sub-studies relevant to the clinical development of ticagrelor in atherothrombotic disease, categorised by clinical disease and treatment strategy.
Short name (year published) | Study population | Intervention | Comparator | Primary endpoint(s) | Key safety endpoint(s) |
PLATO (2009) [12] | 18,624 patients hospitalised with ACS | Ticagrelor (180 mg LD, 90 mg BD MD) plus aspirin 75–325 mg OD for 12 months | Clopidogrel (300–600 mg LD, 75 mg MD) plus aspirin 75–325 mg OD for 12 months | Death from vascular cause, MI or stroke at 12 months: 9.8% vs. 11.7%; Hazard ratio (HR), 0.84; 95% confidence interval (CI) 0.77–0.92; P |
Major bleeding at 12 months: 11.6% vs. 11.2%; HR, 1.04; 95% CI 0.95–1.13; P = 0.43 |
PEGASUS-TIMI 54 (2015) [13] | 21,162 patients with prior spontaneous MI in the last 1–3 years and an additional atherothrombotic risk factor* | Ticagrelor 90 mg (T90) or 60 mg (T60) BD plus aspirin 75–150 mg OD for 36 months | Placebo plus aspirin 75–150 mg OD for 36 months | CV death, MI, or stroke at 3 years: | TIMI major bleeding at 3 years: |
T90: 7.9% vs. 9.0%; HR, 0.85; 95% CI 0.75–0.96; P = 0.008 | T90: 2.6% vs. 1.1%; HR, 2.69; 95% CI 1.96–3.70; P | ||||
T60: 7.8% vs. 9.0%; HR, 0.84; 95% CI 0.74–0.95; P = 0.004 | T60: 2.3% vs. 1.1%; HR, 2.32; 95% CI 1.68–3.21; P | ||||
DACAB (2018) [14] | 500 patients with an indication for elective coronary artery bypass graft surgery. 1460 saphenous vein grafts were inserted | Ticagrelor 90 mg BD plus aspirin (100 mg OD) or alone for 1 year | Aspirin 100 mg OD for 1 year | Graft patency at 1 year: DAPT: 88.7% vs. 76.5%; RR, 0.48; 95% CI 0.31–0.74; P |
Graft patency at 7 days: DAPT: 94.9% vs. 91.1%; RR, 0.58; 95% CI 0.30–1.14; P = 0.11 |
Ticagrelor alone: 82.8% vs. 76.5%; RR, 0.73, 95% CI 0.51–1.06; P = 0.10 | Ticagrelor alone: 94.3% vs. 91.1%; RR, 0.65, 95% CI 0.36–1.18; P = 0.17 | ||||
ISAR-REACT 5 (2019) [15] | 4018 patients hospitalised with ACS for whom an invasive evaluation was scheduled. Treatment: 84% PCI and 2.1% CABG | Ticagrelor (180 mg LD, 90 mg BD MD) based strategy for 12 months | Prasugrel (60 mg LD, 10 mg or 5 mg (if |
Death, MI or stroke at 1 year: 9.3% vs. 6.9%; HR, 1.36; 95% CI 1.09–1.70; P = 0.006 | Bleeding Academic Research Consortium (BARC) type 3, 4, or 5 bleeding at 1 year: 5.4% vs. 4.8%; HR, 1.12; 95% CI 0.83–1.51; P = 0.46 |
THEMIS (2019) [16] | 19,220 patients with stable CAD, type 2 diabetes and no prior MI or stroke | Ticagrelor (90 mg initially, then reduced to 60 mg) BD plus aspirin 75–150 mg OD for 54 months | Placebo plus aspirin 75–150 mg OD for 54 months | CV death, MI, or stroke: 7.7% vs. 8.5%; HR, 0.90; 95% CI 0.81–0.99; P = 0.04 | TIMI major bleeding: 2.2% vs. 1.0%; HR, 2.32; 95% CI 1.82–2.94; P |
THALES (2020) [17] | 11,016 patients with acute non-cardioembolic, non-severe ischaemic stroke (National Institutes of Health Stroke Score (NIHSS) |
Ticagrelor (180 mg LD, 90 mg BD MD) plus aspirin (300–325 mg LD, 75–100 mg OD MD) for 34 days | Placebo plus aspirin (300–325 mg LD, 75–100 mg OD MD) for 34 days | Stroke or death at 30 days: 5.5% vs. 6.6%; HR, 0.83; 95% CI 0.71–0.96; P = 0.02 | GUSTO severe bleeding at 30 days: 0.5% vs. 0.1%; HR, 3.99; 95% CI 1.74–9.14; P = 0.001 |
ALPHEUS (2020) [18] | 1910 patients with stable CAD with an indication for PCI and at least 1 high-risk feature† | Ticagrelor (180 mg LD, 90 mg BD MD) (87% on aspirin at admission) for 30 days | Clopidogrel (300–600 mg LD, 75 mg OD MD) (85% on aspirin at admission) for 30 days | PCI-related type 4 (a or b) MI or major myocardial injury at 48 h: 35% vs. 36%; OR, 0.97; 95% CI 0.80–1.17; P = 0.75 | Major bleeding (BARC 3 or 5) at 48 h: |
Minor bleeding (BARC 1 or 2) at 30 days: 11% vs. 8%; OR, 1.54; 95% CI 1.12–2.11; P = 0.007 | |||||
* One of the following: |
Platelets have a critical function within the vascular system to regulate
haemostasis. Injury to the vascular endothelium exposes underlying extracellular
matrix and prothrombotic factors, resulting in a cascade of events that stimulate
platelet activation, a process involving structural shape change, degranulation,
and platelet aggregation. Degranulation involves the release of pro-inflammatory
and prothrombotic
The nomenclature assigned to G-protein-coupled receptors that are activated by
nucleotides, such as ADP, is P2Y. To date, eight of these purinergic receptors
have been identified [26], of which two are functionally present on the surface
of platelets: G
The primary member of the G
Antiplatelet drugs that targeted the P2Y
Considering that the P2Y
Pharmacology of ticagrelor. Morphine slows gastric
emptying and therefore may delay the onset of action of ticagrelor, which is
absorbed in the small intestine. Once in the circulation, ticagrelor acts
directly, as well as indirectly via ticagrelor active metabolite (TAM), as (1) a
non-competitive antagonist and inverse agonist of the P2Y
Ticagrelor, previously identified as AZD6140, belongs to the
cyclopentyl-triazolopyrimidine class of P2Y
Chemical structures of adenosine, adenosine triphosphate, AR-C124910XX (ticagrelor active metabolite) and ticagrelor.
Interestingly, ticagrelor exerts a well-documented antagonistic effect on
platelet and erythrocyte equilibrative nucleoside transporter (ENT)1 (Fig. 2),
potentially resulting in an increase in extracellular adenosine by inhibiting
cellular adenosine uptake [10, 47, 48, 49]. Due to its low potency as an ENT1
antagonist relative to its high potency as a P2Y
Considering that studies have shown ticagrelor to impact coronary blood flow responses and severity of adenosine-mediated side effects during adenosine infusions [56, 58], it remains possible that ticagrelor affects adenosine concentrations in localised tissues. Hypothetically there may be local enhancement of adenosine concentration at the platelet cell membrane, which may produce therapeutic effects that are not reflected by measurements of systemic plasma adenosine level [31]; however, this mechanism remains to be proven and some preclinical studies have not confirmed a beneficial adenosine-mediated effect of ticagrelor on infarct size [59].
The anti-inflammatory effects of ticagrelor may be an important contributor to
clinical outcomes. In an endotoxaemia model, there was evidence that ticagrelor
exhibited greater anti-inflammatory properties when compared to clopidogrel. Both
suppressed the release of tumour necrosis factor-
An in vitro study identified that ticagrelor, but not the clopidogrel
active metabolite, activates endothelial nitric oxide synthase [65]. These
effects were independent of P2Y
Ticagrelor has a mean absolute oral bioavailability of 36% [66]. The absorption
of ticagrelor is rapid and reaches a maximum plasma concentration (t
There are several clinically significant pharmacological interactions between
ticagrelor and other medications. While ticagrelor is primarily a substrate of
CYP3A4, it also mildly inhibits the same isozyme [72], and therefore
co-administration with CYP3A4 substrates with a narrow therapeutic index (e.g.,
ergot alkaloids) is discouraged due to an increased risk of elevated exposure
[73]. In addition, strong CYP3A4 inhibitors (e.g., ketoconazole and
clarithromycin) are contraindicated since they potentially lead to excessive
ticagrelor levels and strong CYP3A inducers (e.g., phenytoin and carbamazepine)
are discouraged since they may risk subtherapeutic ticagrelor levels [50, 73].
With greater relevance to cardiovascular disease, the C
Ticagrelor is also a substrate and inhibitor of the intestinal P-glycoprotein
transporter and administration of ticagrelor during treatment with digoxin (a
P-glycoprotein substrate) led to 75% and 28% increases in the C
Various studies have identified that the administration of morphine delays the
absorption and onset of action of oral P2Y
There is currently no evidence that the pharmacogenetic profile of ticagrelor impacts the clinical outcome in patients with ACS. In a genome-wide association study, three single-nucleotide polymorphisms were identified (SLCO1B1, UGT2B7, CYP3A4) that influenced the pharmacokinetics of ticagrelor and its active metabolite, but not to an extent that interfered with the safety or efficacy of the regimen [88]. In addition, common variations in the ENT1 genotype are not associated with altered clinical outcomes following the administration of ticagrelor or clopidogrel [89].
Both ticagrelor and clopidogrel are widely used oral P2Y
As a feature of thienopyridines, clopidogrel irreversibly antagonises P2Y
Unlike thienopyridines, ticagrelor binds reversibly to P2Y
To achieve acceptable outcomes, the antithrombotic efficacy must be balanced against the risk of bleeding and therefore a pharmacological agent that is capable of reversing the haemostatic effects of ticagrelor is highly desirable for use in emergency procedures where the risk of bleeding is increased. Bentracimab (PB2452) is an antigen-binding fragment antidote to ticagrelor that has demonstrated effective neutralisation properties both in vitro and in mice [110] and healthy volunteers [111]. A numerical improvement in ADP-induced platelet aggregation, blood loss and survival in response to PB2452 in pigs provides further encouragement [112], and pharmacological characterisation [113] and phase IIB and phase III studies are underway (ClinicalTrials.gov Identifier: NCT04122170 and NCT04286438 respectively). An alternative approach in patients undergoing urgent or emergency cardiopulmonary bypass surgery or extracorporeal membrane oxygenation is reducing ticagrelor plasma levels using haemadsorption with the CytoSorb cartridge system that can be linked with the bypass circuit and is CE-marked for this purpose [114] (ClinicalTrials.gov Identifier: NCT04131959).
The Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs.
clopidogRel in non-ST-segment Elevation myocardial infarction (DISPERSE)-2 study
investigated the safety, tolerability and initial efficacy of two doses of
ticagrelor (90 mg or 180 mg BD) plus aspirin, compared with standard clopidogrel
(300 mg loading dose, 75 mg OD) DAPT in 984 patients with NSTE-ACS [115]. There
was no difference in the incidence of overall bleeding at 4 weeks (ticagrelor 90
mg, 180 mg and clopidogrel; 9.8%, 8.0% and 8.1% respectively; P =
0.43 and P = 0.96, respectively, vs. clopidogrel) between the groups.
The results also suggested good tolerability of ticagrelor, but showed a higher
incidence of dyspnoea (10.5%, 15.8% and 6.4%; P = 0.07 and P
As a result of a worldwide collaborative effort, studies have highlighted the benefits of using ticagrelor-based DAPT for the secondary prevention of MACE in ACS patients, up to one year and beyond, in post-ACS patients at high risk of ischaemic events.
18,624 patients with ACS were recruited to the double-blind randomised Platelet
Inhibition and Patient Outcomes (PLATO) study to compare the efficacy of
ticagrelor and clopidogrel, administered with aspirin [12]. Ticagrelor not only
proved superior at reducing the primary composite endpoint of vascular death, MI
and stroke at 12 months (9.8% [ticagrelor] vs. 11.7% [clopidogrel]; HR, 0.84;
95% CI 0.77–0.92; P
Before the Prevention of Cardiovascular Events in Patients with Prior Heart
Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin
(PEGASUS-) Thrombolysis in Myocardial
Infarction (TIMI) 54 study, it was unclear if DAPT should be carried on beyond 12
months post-MI for patients at high risk of developing further ischaemic events
[13, 116]. This prospective study investigated the efficacy of two doses of
ticagrelor versus placebo, combined with low-dose aspirin, over a 3-year period
in 21,126 stable patients with a history of MI (median 1.7 years prior), who were
at least 50 years old and had an additional atherothrombotic risk factor (Table 1). Ticagrelor was studied for the first time at a dose of 60 mg BD in addition
to further study of the 90 mg BD dose. Both ticagrelor doses significantly
reduced the incidence of MACE (7.9% [ticagrelor 90 mg], 7.8% [ticagrelor 60 mg]
and 9.0% [placebo]; P = 0.008 and P = 0.004 vs. placebo,
respectively). Cardiovascular deaths alone were not significantly reduced versus
placebo in the overall trial population although there was evidence of a reduced
risk of CAD-related deaths (90 mg: HR, 0.73 [95% CI 0.56–0.95]; 60 mg: HR, 0.80
[95% CI 0.62–1.04]). Ticagrelor increased the incidence of major (2.6%, 2.3%
and 1.1%; P
In response to the publication of the PEGASUS-TIMI 54 study, all active or
newly-enrolled participants in The Effect of Ticagrelor on Health Outcomes in
Diabetes Mellitus Patients Intervention Study (THEMIS) [16] were switched to or
started on, respectively, the lower dose of ticagrelor (60 mg BD). Primary and
supplementary analysis showed consistent results independent of the dose. THEMIS
was a randomised double-blind trial that sought to determine if adding ticagrelor
to aspirin improves outcomes in patients with stable CAD and T2DM with no history
of MI or stroke. The results showed that addition of ticagrelor to aspirin
reduced the incidence of MACE (7.7% [ticagrelor] vs. 8.5% [placebo]; HR, 0.90;
95% CI 0.81–0.99; P = 0.04) but conversely increased major bleeding
(2.2% vs. 1.0%; HR, 2.32; 95% CI 1.82–2.94; P
The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial was a recent open-label randomised controlled trial (RCT) that compared two different treatment strategies in 4018 patients with ACS who were scheduled for invasive evaluation (i.e., coronary angiography) [15]. Following randomisation, a loading dose of ticagrelor was immediately administered to all patients randomised to ticagrelor whereas only STEMI patients randomised to prasugrel were intended to receive the loading dose of prasugrel before coronary angiography and those with NSTE-ACS underwent coronary angiography first, following which they received a loading dose of prasugrel only if proceeding to PCI, reflecting the evidence that prasugrel increases the risk of major bleeding if administered pre-PCI in this population [120]. ISAR-REACT 5 found that the ticagrelor-based strategy was less effective at preventing MACE (9.3% [ticagrelor] vs. 6.9% [prasugrel]; HR, 1.36; 95% CI 1.09–1.70; P = 0.006) compared to the prasugrel-based strategy and that there was no difference in major bleeding (5.4% vs. 4.8%; HR, 1.12; 95% CI 0.83–1.51; P = 0.46) after one year. This finding was unexpected as the trial was testing the hypothesis that ticagrelor would be superior to prasugrel. In addition to the open-label design of the study, there were a number of considerations that indicate the need for caution in translating the findings to clinical practice: (1) patients were randomised within 1–2 hours of coronary angiography and so any benefit of ticagrelor pre-treatment in patients waiting longer for coronary angiography was not assessed; (2) the majority of patients had femoral artery access for their procedure, which does not reflect contemporary optimal practice and would have disadvantaged the pre-treatment approach with ticagrelor; (3) approximately one-third of the benefit of prasugrel was through reduction in stent thrombosis, which is not consistent with the platelet inhibition profiles of the two drugs and therefore likely indicates poor adherence in the ticagrelor group, raising questions about the counselling and management of the study patients since better outcomes have been achieved in experienced centres; and (4) the better outcomes with prasugrel also partly reflected lower non-cardiovascular mortality, which is inconsistent with the results of the much larger phase-III studies and therefore suggests the play of chance. Poor adherence may have been a particular issue in the patients without diabetes since patients with diabetes did equally well with the ticagrelor-based and prasugrel-based strategies in the trial [121]. Large-scale observational data indicate similar outcomes with ticagrelor and prasugrel in PCI-treated MI patients [122, 123]. Reports of greater platelet inhibition with prasugrel compared with ticagrelor maintenance therapy are likely based on artefact related to the use of multiple electrode plate aggregometry since studies with other platelet function tests have demonstrated greater platelet inhibition during maintenance therapy with ticagrelor [107, 124] and this is consistent with the different development strategies for the two drugs [123].
PCI is a procedure frequently performed in patients with CAD, usually involving the insertion of at least one drug-eluting stent (DES) to treat and prevent the progression of focal coronary artery stenosis. Approximately 60% of ACS patients undergo PCI when hospitalised [12]. A range of innovative studies involving ticagrelor have recently been conducted with the aim to optimise patient outcomes by reducing the burden of ischaemia and/or bleeding for those who have received PCI by tailoring the duration and combination of antiplatelet drugs.
Two meta-analyses [125, 126] collated ten RCTs to determine the length of time
that DAPT should be administered following DES insertion during PCI. They both
favoured a shorter duration of DAPT (
A prespecified subgroup analysis of the THEMIS study (median follow-up of 3.3
years) demonstrated an improved benefit-to-risk ratio for ticagrelor in patients
with a PCI procedure in the past [127]. In this subgroup, there was a lower rate
of both MACE (7.3% [ticagrelor] vs. 8.6% [placebo]; HR, 0.85; 95% CI
0.74–0.97; P = 0.013) and the exploratory net clinical benefit endpoint
of irreversible harms (9.3% vs. 11.0%; HR, 0.85; 95% CI 0.75–0.95; P
= 0.005), involving a composite of all-cause mortality, MI, stroke, fatal
bleeding or intracranial haemorrhage. In contrast, patients with no history of
PCI appeared to obtain no net clinical benefit from ticagrelor based-DAPT
according to the latter composite endpoint (11.1% vs. 10.5%; HR, 1.06; 95% CI
0.93–1.21; P = 0.39). TIMI-defined major bleeding was significantly
more frequent when receiving ticagrelor regardless of whether or not the patient
had a history of PCI (2.0% vs. 1.1%; HR, 2.03; 95% CI 1.48–2.76; P
Considering that increasing the efficacy of antiplatelet regimens is accompanied by a penalty in bleeding risk, another novel strategy that has gained attention is the discontinuation of aspirin, after a short period of DAPT, at an early stage after PCI (Table 2). While de-escalating antiplatelet therapy is unlikely to reduce ischaemic risk, it may improve safety yet maintain efficacy. This may be particularly important in the context of severe post-PCI bleeding, which poses a similar mortality risk compared with MI [128, 129].
Short name (year published) | Study population | Intervention | Comparator | Primary endpoint(s) | Key safety endpoint(s) |
SOCRATES (2016) [19] | 13,199 patients with acute, non-cardioembolic, non-severe ischaemic stroke (NIHSS |
Ticagrelor (180 mg LD, 90 mg BD MD) plus placebo for 90 days | Aspirin (300 mg LD, 100 mg OD MD) plus placebo for 90 days | Ischaemic or haemorrhagic stroke, MI or death at 90 days: 6.7% vs. 7.5%; HR, 0.89; 95% CI 0.78–1.01; P = 0.07 | PLATO major bleeding at 90 days: 0.5% vs. 0.6%; HR, 0.83; 95% CI 0.52–1.34; P = 0.45 |
EUCLID (2017) [20] | 13,885 patients with either previous revascularisation of lower limbs or haemodynamic evidence due to symptomatic PAD | Ticagrelor 90 mg BD for 36 months | Clopidogrel 75 mg OD for 36 months | CV death, MI or ischaemic stroke: 10.8% vs. 10.6%; HR, 1.02; 95% CI 0.92–1.13; P = 0.65 | TIMI major bleeding: 1.6% vs. 1.6%; HR, 1.10; 95% CI 0.84–1.43; P = 0.49 |
TIMI minor bleeding: 1.2% vs. 1.0%; HR, 1.32; 95% CI 0.96–1.83; P = 0.09 | |||||
GLOBAL LEADERS (2018) [21] | 15,968 patients receiving a DES for stable CAD (53.1%) or ACS (46.9%), between angiography and PCI | Aspirin 75–100 mg OD plus ticagrelor 90 mg BD for 1 month, followed by ticagrelor 90mg BD for 23 months | Aspirin 75–100 mg plus either clopidogrel 75mg OD (stable CAD) or ticagrelor 90mg BD (ACS) for 12 months, then aspirin for 12 months | All-cause mortality or new Q-wave MI at 730 days: 3.81% vs. 4.37%; RR, 0.87; 95% CI 0.75–1.01; P = 0.073 | BARC grade 3 or 5 bleeding: 2.04% vs. 2.12%; RR, 0.97; 95% CI 0.78–1.20; P = 0.77 |
TWILIGHT (2019) [22] | 7119 high-risk patients* who underwent PCI for either stable CAD or NSTE-ACS, and 3 event-free months of ticagrelor 90 mg BD plus aspirin 81–100 mg OD | Ticagrelor 90 mg BD plus placebo for 12 months | Aspirin 81–100 mg OD plus ticagrelor 90 mg BD for 12 months | BARC grade 2, 3 or 5 bleeding at 1 year: 4.0% vs. 7.1%; HR, 0.56; 95% CI 0.45–0.68; P |
All-cause mortality, non-fatal MI or non-fatal stroke at 1 year: 3.9% vs. 3.9%; HR, 0.99; 95% CI 0.78–1.25; P (noninferiority) |
TICO (2020) [23] | 3065 patients treated with DES for ACS | Aspirin 100 mg OD plus ticagrelor 90 mg BD for 3 months, then ticagrelor 90 mg BD for 9 months | Aspirin 100 mg OD plus ticagrelor 90 mg BD for 12 months | Net adverse clinical events† at 12 months: 3.9% vs. 5.9%; HR, 0.66; 95% CI 0.48–0.92; P = 0.01 | TIMI major bleeding at 12 months: 1.7% vs. 3.0%; HR, 0.56; 95% CI 0.34–0.91; P = 0.02 |
MACE at 12 months: 2.3% vs. 3.4%; HR, 0.69; 95% CI 0.45–1.06; P = 0.09 | |||||
* At least one additional clinical (at least 65 years old, female gender,
troponin positive ACS, established vascular disease, diabetes treated with
medication, CKD) and one angiographic (multivessel CAD, total stent length |
The Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation (GLOBAL LEADERS) study sought to determine if ticagrelor-based DAPT for one month followed by ticagrelor monotherapy was superior to standard DAPT therapy (aspirin plus either ticagrelor for ACS or clopidogrel for CCS) for 12 months followed by aspirin monotherapy, over a two-year period following DES implantation in 15,968 patients [21]. The findings demonstrated no difference in the ambitious primary composite endpoint of all-cause mortality or new Q-wave MI (3.81% [1-month DAPT] vs. 4.37% [12-month DAPT]; risk ratio [RR], 0.87; 95% CI 0.75–1.01; P = 0.073) or the key safety endpoint of major bleeding (2.04% vs. 2.12%; RR, 0.97; 95% CI 0.78–1.20; P = 0.77). In a recent post-hoc subgroup analysis of the ACS cohort that evaluated clinical outcomes between 31 and 365 days post-randomisation, thereby exclusively comparing ticagrelor monotherapy with ticagrelor-based DAPT, there remained no significant difference in the primary endpoint (1.5% [monotherapy] vs. 2.0% [DAPT]; HR, 0.73; 95% CI 0.51–1.03; P = 0.073) but a significant reduction in major bleeding was observed (0.8% vs. 1.5%; HR, 0.52; 95% CI 0.33–0.81; P = 0.004) [130]. While the results of this analysis are encouraging, they must be considered as hypothesis-generating in light of their post-hoc nature, although the reduction in bleeding with aspirin cessation is predictable due to the subsequent increase in platelet reactivity and avoidance of aspirin-related gastrotoxicity [131].
Furthermore, in the Ticagrelor with Aspirin or Alone in High-Risk Patients after
Coronary Intervention (TWILIGHT) study, 9006 patients who were determined to be
at high risk of bleeding or ischaemia received DAPT with ticagrelor and aspirin
for three months following PCI with DES for NSTE-ACS (65%) or CCS (35%) [22].
Of those who did not suffer from a disqualifying event, 7119 continued to take
ticagrelor and were randomised to either receive placebo or continue with aspirin
for a duration of 12 months. Reflecting the priority of the experimental regimen
to provide a better safety profile than the standard-treatment comparator while
maintaining safe antithrombotic protection, the primary endpoint was a composite
of BARC (Bleeding Academic Research Consortium)-defined grade 2, 3 or 5 bleeding
and the key secondary endpoint was a composite of all-cause mortality, non-fatal
MI or non-fatal stroke. The results showed that the primary endpoint occurred
significantly less frequently during ticagrelor monotherapy than DAPT (4.0%
[monotherapy] vs. 7.1% [DAPT]; HR, 0.56; 95% CI 0.45–0.68; P
In a pre-specified subgroup analysis, TWILIGHT-ACS highlighted that ticagrelor
monotherapy provided greater magnitude of reduced bleeding in 4614 patients with
NSTE-ACS (3.6% [monotherapy] vs. 7.6% [DAPT]; HR, 0.47; 95% CI 0.36–0.61;
P
Considering the evidence, it is becoming increasingly apparent that a tailored approach is required for ticagrelor-treated patients, particularly those with ACS. While the management of modifiable risk factors and development of thin-strut, biocompatible DES is improving clinical outcomes [8, 133], current evidence suggests the need for a dichotomization of treatment whereby those with unmodifiable risk factors for atherothrombotic events, but with a low risk of bleeding, receive long-term DAPT and those with controllable risk factors or a high risk of bleeding receive ticagrelor monotherapy following short-term DAPT [134].
Ticagrelor may not provide benefit in low-risk individuals undergoing elective
PCI. With the aim to reduce prognostically-important periprocedural myonecrosis
[135], the recently-published Assessment of Loading with the P2Y
The severity of ischaemia during STEMI and the susceptibility to further
infarction of adjacent myocardial tissues makes it a particularly time-sensitive
event, whereby the optimal choice of agent and timing requires careful
consideration and elaboration. In a PLATO subgroup of patients with STEMI or left
bundle branch block planned for primary PCI, ticagrelor remained superior to
clopidogrel at preventing MACE at 12 months [136]. This benefit was independent
of the extent of ST elevation at presentation and ticagrelor was not associated
with any improvement in resolution of ST elevation, implying that its observed
benefit was dependent on prevention of recurrent vascular events rather than
superior effects on early perfusion or protection from reperfusion injury [137].
These observations were contrary to the findings from pre-clinical animal
experiments demonstrating that early exposure of ticagrelor has pleiotropic
cardioprotective effects that attenuate myocardial infarct size following
coronary occlusion and reperfusion [138], to a greater degree than clopidogrel
[139, 140]. This has implications for the choice of initial antiplatelet agent in
the management of STEMI patients [141]. It has been observed that the enteric
absorption of ticagrelor is often delayed in STEMI patients, especially when
opiates such as morphine are co-administered for pain relief [76, 77, 78, 79]. This
phenomenon may explain the limited early benefit of ticagrelor and lack of
difference in angiographic outcomes seen in the PLATO angiographic substudy,
since rapid performance of PCI likely provided insufficient time to allow
ticagrelor’s effects to become apparent in opiate-treated patients [142].
Administration of a parenteral P2Y
Around 10% of patients diagnosed with an ACS event are treated by CABG [12], which is also an option for revascularisation in selected patients with CCS [2]. Factors that might favour CABG over PCI as a revascularisation strategy include triple-vessel or left main coronary artery disease, particularly in patients with diabetes mellitus and those with chronic total occlusions of major coronary vessels [145]. A common complication occurring after CABG is graft occlusion, which can lead to recurrent ACS (including manifestation as sudden death), angina, or heart failure [146]. As a major surgical procedure, CABG carries a significant risk of perioperative bleeding that must be balanced against any benefits of improved graft patency and broader protection from MACE that antiplatelet therapy may offer [147].
An analysis of ticagrelor vs. the then standard-of-care clopidogrel in
aspirin-treated ACS patients undergoing CABG was included in the PLATO study
[148]. Out of the trial population of 18,624, 1261 underwent CABG within seven
days of receiving study medication. Though underpowered to test robustly, there
was evidence that the primary endpoint of MACE at 12 months occurred less
frequently when receiving ticagrelor versus clopidogrel (10.6% vs. 13.1%,
respectively; HR, 0.84; 95% CI 0.60–1.16; P = 0.29). Moreover, there
was a strong signal of lower all-cause mortality (4.7% vs. 9.7%; HR, 0.49; 95%
CI 0.32–0.77; P
Ticagrelor-based DAPT has also been compared with aspirin alone in patients
undergoing CABG. In the Different Antiplatelet Therapy Strategy After Coronary
Artery Bypass Graft Surgery (DACAB) trial, adding ticagrelor to aspirin led to
better saphenous vein graft patency compared to aspirin alone (RR, 0.48; 95% CI
0.31–0.74; P
Ticagrelor may offer advantages over thienopyridines to ACS patients awaiting
CABG as, due to its reversible binding, it has a more rapid offset [104].
Furthermore, there are emerging strategies for more prompt reversal of
ticagrelor’s effects prior to CABG such as an haemadsorbent filter or infusion of
a monoclonal antibody against the drug, neither of which are feasible for
thienopyridines due to their irreversible action [111, 114]. Several
observational studies have examined how long before CABG ticagrelor should be
withheld in order to avoid excess bleeding risk. Data from a Swedish registry
suggested that discontinuation
Ischaemic stroke is a common and often catastrophic condition. The thrombotic subtype shares a common pathophysiological mechanism and risk-factor profile with CAD [155]. Therefore, antiplatelet drugs may reduce the risk of thrombotic stroke, but conversely increase the risk of bleeding, including intracranial bleeding events. The mainstay of pharmacological management of those at high risk of stroke has been single antiplatelet therapy, which has demonstrated a clear benefit at reducing the risk of large-artery atherothrombotic stroke but not small vessel occlusion or cardiac thromboembolism [156], with either aspirin or clopidogrel. There is some evidence that clopidogrel may be modestly superior to aspirin, particularly in patients with a history of stroke or PAD [157]. Given ticagrelor may offer pharmacodynamic advantages over aspirin or clopidogrel, it has therefore been hypothesised that ticagrelor may offer superior clinical efficacy after ischaemic stroke.
The Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or
Ticagrelor and Patient Outcomes (SOCRATES) trial was a multi-centre double-blind
RCT involving 13,199 patients with acute (
The Acute Stroke or Transient Ischaemic Attack Treated with Ticagrelor and Acetylsalicylic Acid for Prevention of Stroke and Death (THALES) study was a double-blind, placebo-controlled RCT [17] in a similar population to SOCRATES that also included patients with symptomatic arterial stenosis. This study showed that ticagrelor combined with aspirin reduced the incidence of the composite endpoint of stroke or death compared with aspirin monotherapy at 30 days (5.5% [DAPT] vs. 6.6% [aspirin]; HR, 0.83; 95% CI 0.71–0.96; P = 0.02). DAPT also reduced the incidence of ischaemic stroke (5.0% vs. 6.3%; HR, 0.79; 95% CI 0.68–0.93; P = 0.004) versus aspirin alone; however, there was no difference in overall disability (23.8% vs. 24.1%; HR, 0.98; 95% CI 0.89–1.07; P = 0.61) between the two groups, and the rate of severe bleeding was significantly higher in the ticagrelor group at 30-days follow-up (0.5% vs. 0.1%; HR, 3.99; 95% CI 1.74–9.14; P = 0.001).
Atherosclerosis can also lead to PAD, for example manifesting as lower extremity artery disease or carotid artery stenosis. Patients with PAD are also at an increased risk of developing cerebral or myocardial ischaemia as a result of widespread atherosclerotic disease. Clopidogrel has previously demonstrated superiority over aspirin in reducing the risk of MACE (relative risk reduction, 23.8%; 95% CI 8.9–36.2; P = 0.003) in a subgroup of patients with PAD [157], and a post-hoc analysis of the PLATO study suggested similar beneficial trends during ticagrelor-based DAPT over clopidogrel-based DAPT in patients with ACS and PAD [158].
The Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) double-blind, event-driven trial investigated the use of ticagrelor versus clopidogrel monotherapy on the composite risk of MACE in 13,885 patients with symptomatic PAD over a median period of 36 months [20]. The study showed that ticagrelor was not superior to clopidogrel in preventing MACE (10.8% [ticagrelor] vs. 10.6% [clopidogrel]; HR, 1.02; 95% CI 0.92–1.13; P = 0.65), acute limb ischaemia (1.7% vs. 1.7%; HR, 1.03; 95% CI 0.79–1.33; P = 0.85) or major bleeding (1.6% vs. 1.6%; HR, 1.10; 95% CI 0.84–1.43; P = 0.49). Ticagrelor did result in greater rates of discontinuation than clopidogrel (15.4% vs. 11.1%, respectively), mainly as a result of dyspnoea and bleeding. Based on this evidence, use of ticagrelor monotherapy cannot currently be recommended for event prevention in those with PAD, unless they have another indication. This is reflected in the European Society of Cardiology (ESC) PAD 2017 guidelines [159]. The lack of benefit of ticagrelor, which offers greater potency and consistency of platelet inhibition than clopidogrel, was surprising and further work is required to determine whether pleiotropic effects of clopidogrel may be relevant during long-term treatment in this population with extensive atherosclerotic disease, such as related to off-target anti-inflammatory effects [64].
Throughout clinical trials, ticagrelor-associated dyspnoea has been consistently observed [16, 104, 115, 160]. In an analysis of the PLATO study, dyspnoea was reported in 14.5% of those receiving ticagrelor vs. 8.7% receiving clopidogrel, the excess being attributable to an effect of ticagrelor. Very few events were of severe intensity (0.4% vs. 0.3%, respectively). 27.3% vs. 20.1% of dyspnoeic events had no identifiable aetiology. Characteristics such as increased age and waist circumference as well as medical conditions including diabetes and chronic kidney disease (CKD) were associated with an increased risk of developing dyspnoea when treated with ticagrelor [160].
Dyspnoea during ticagrelor therapy does not appear to be associated with any changes in cardiac, pulmonary or metabolic function, whether in patients with CCS [161] or ACS [162]. Ticagrelor-related dyspnoea is typically of mild or moderate intensity, most often develops within one week of the initiation of treatment (median 23 days), and contributes to a low number of patients (approximately 1%) discontinuing the regimen and switching to a thienopyridine [160]. There appears to be a modest association between ticagrelor plasma levels and dyspnoea.
In patients who reported dyspnoea in the PLATO study, excluding those in whom it was MI-related, the effect of ticagrelor, compared with clopidogrel, on MACE appeared consistent with the main PLATO study results (8.8% vs. 10.4%; adjusted HR, 0.91; 95% CI 0.67–1.23; adjusted P = 0.542) [12]. There was also no impact on bleeding risk [160]. It therefore appears that ticagrelor-related dyspnoea is independent of any physical manifestations of disease and does not affect the efficacy or safety profile of ticagrelor therapy.
A perturbation in the afferent reflex carried by sensory chemoreceptor,
mechanoreceptor or vagal C-fibres from the lungs and respiratory muscles may all
contribute to an inappropriate perception of dyspnoea in the sensorimotor cortex
of the brain [163]. Two main mechanisms have been proposed to explain how
ticagrelor treatment can induce dyspnoea [164]. The first relates to ENT1
antagonism resulting in an elevated concentration of extracellular adenosine, a
compound that has been associated with dyspnogenic effects in humans [165]. This
is supported by the fact that theophylline, an adenosine receptor antagonist,
blocks the potentiation of adenosine-induced dyspnoea by ticagrelor [56]. Against
this theory is that dipyridamole, which has greater potency than ticagrelor at
preventing adenosine reuptake, has not been associated with dyspnoea [166]. The
second relates to the inhibition of putative P2Y
In terms of management, one of the major challenges facing clinicians is to determine whether dyspnoea in a patient is related to a serious pathology or a side-effect of the medication. Ticagrelor-induced dyspnoea is generally a diagnosis of exclusion, following a thorough history and examination, but some mild cases that are not associated with limitation of exercise capacity, orthopnoea or nocturnal dyspnoea can be readily attributed to ticagrelor and reassurance provided, particularly in patients who have been successfully revascularised. While persistent and intolerable ticagrelor-induced dyspnoea is uncommon, currently the only proven management strategy is discontinuation [166] although dose reduction from 90 mg BD to 60 mg BD may be an alternative option to try if dyspnoea is not severe.
In the PLATO study, ticagrelor was associated with a greater incidence of
asymptomatic ventricular pauses of 3 seconds or more in the first week (5.8%
[ticagrelor] vs. 3.6% [clopidogrel]; P = 0.01), and a greater increase
in baseline levels of serum uric acid (mean
A major challenge facing clinicians is patients who have indications for both
dual antiplatelet therapy and oral anticoagulant therapy, most commonly as a
result of patients with atrial fibrillation being treated with PCI. Recent trials
have indicated that vitamin K antagonists (VKA), such as warfarin, carry
substantially higher risk of life-threatening bleeding, most notably intracranial
haemorrhage, compared with non-VKA oral anticoagulants (NOAC), including when
used in conjunction with antiplatelet drug regimens [171, 172, 173, 174]. The 2
This review has presented novel developments in antiplatelet therapy and has
emphasised the role of ticagrelor. It is evident that the choice of
pharmacological agents and the duration of treatment is dependent on the risk
factors and clinical features of the individual patient. The clinical development
of ticagrelor for use in CAD initially placed it as a substitute to clopidogrel
in the context of DAPT i.e., in combination with baseline aspirin therapy.
However, a post-hoc analysis of the PLATO trial found a significant
interaction between high (
Based on a variety of studies, it is clear that combining aspirin and ticagrelor
has additive effects [42, 181] and may be required long term in certain patient
populations that are at high risk of arterial thrombotic events. For example,
PEGASUS-TIMI 54 and THEMIS-PCI consisted of high-risk individuals who derived
greater antithrombotic benefit from DAPT than aspirin alone. In addition, the
SOCRATES and THALES trials showed that patients with ischaemic stroke derived no
benefit in ischaemic risk from ticagrelor alone vs. aspirin, but did benefit from
DAPT. For three of these studies, the superior efficacy of DAPT also came at a
cost of substantially increased risk of bleeding. Therefore, it appears that
combining P2Y
The European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) publish regular guidelines that represent the views of experts in cardiology, based on the current knowledge and understanding of cardiac conditions and management at the time of publication. The following highlight the latest guidelines and represents the class of recommendation (I–III) and the level of evidence (A–C) that are relevant to the use of ticagrelor in CAD.
The ESC 2017 [5] and ACC Foundation/AHA 2013 [6] STEMI guidelines both
recommend the use of ticagrelor (180 mg loading dose, then 90 mg BD maintenance
dose) as a first-line P2Y
The ESC 2020 [3] and AHA/ACC 2014 [4] NSTE-ACS guidelines state that aspirin
plus a P2Y
The ESC 2019 [2] CCS guidelines recommend that an oral P2Y
According to ESC guidelines, for NSTE-ACS and CCS patients with an indication for long-term anticoagulation and a moderate or high risk of stent thrombosis, ticagrelor or prasugrel plus an oral anticoagulant in dual antithrombotic therapy may be considered as an alternative to triple antithrombotic therapy (IIb, C), and are not recommended for use in triple therapy (III, C) [2, 3].
Current ESC recommendations advise 12 months of DAPT with aspirin and a
P2Y
Future work will exploit the reversibility of ticagrelor with the further characterisation and development of methods for reversing ticagrelor’s effects in the event of patients needing urgent surgery or developing major bleeding complications. More work is required to identify which patients are best suited to ticagrelor monotherapy following PCI in order to tailor efficacy and safety according to individual characteristics. When dual antiplatelet therapy is required, further work will assess potential benefits of twice-daily very-low-dose aspirin regimens combined with ticagrelor. Tailoring of the ticagrelor dose according to body weight may also help refine short-term and long-term tolerability of ticagrelor in the future. Learning how ticagrelor can work alongside novel secondary prevention medications will provide opportunities for refinement of secondary prevention of cardiovascular disease.
Ticagrelor is an oral P2Y
AC, Adenylate Cyclase; ACC, American College of Cardiology; ACS, Acute Coronary
Syndrome; ADP, Adenosine Diphosphate; AHA, American Heart Association; ALPHEUS,
Assessment of Loading with the P2Y
NCS and WAEP drafted the manuscript under the supervision of RFS, who edited and approved the final version. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
Not applicable.
We thank Dharshan Giri for his assistance.
WAEP is funded by British Heart Foundation Clinical Research Training Fellowship FS/18/49/33752.
NCS and WAEP declare no conflict of interest.
RFS reports institutional research grants/support from AstraZeneca, Cytosorbents, GlyCardial Diagnostics and Thromboserin; consultancy fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Cytosorbents, GlyCardial Diagnostics, Hengrui, Idorsia, PhaseBio, Portola, Sanofi Aventis and Thromboserin; and honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Intas Pharmaceuticals, Medscape and Radcliffe Cardiology.