The New Dual Antiplatelet Therapy Agents and their Role in Acute Coronary Syndrome

Background: Prasugrel and ticagrelor are two novel antiplatelet agents, which have been subject to large randomized trials to compare their efficacy with clopidogrel for patients with acute coronary syndrome (ACS). Aim: To conduct a systematic review of prasugrel and ticagrelor as alternative therapy to clopidogrel in patients who present with ACS undergoing PCI. Methods: The articles cited in this paper were searched on PubMed, MEDLINE, and Plymouth University’s Metalib database. The search terms used included “dual antiplatelet therapy”, “prasugrel”, “ticagrelor”, and “clopidogrel resistance”. Discussion: The main indications for the use of prasugrel based on current understanding are patients presenting with acute STEMI referred for primary PCI, ACS patients with DM, or those who have a high risk of stent thrombosis. Ticagrelor, on the other hand, may provide optimal benefit for patients with NSTEMI treated with conservative or invasive therapy, those with previous TIA or stroke, advanced age, or small body surface. Conclusion: Prasugrel and ticagrelor have been shown to be adequate P2Y12 antiplatelet therapy alternatives to clopidogrel in the management of patients with ACS. While prasugrel and ticagrelor have both been shown to clinically improve platelet inhibition and significantly reduce the incidence of stent thrombosis compared with clopidogrel therapy, both increase the risk of a significant bleeding incident. Both ticagrelor and prasugrel have been shown to be appropriate and effective treatment alternatives for ACS patients who display clopidogrel treatment resistance or failure. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISBN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, 2014, 22(1): 51-63. doi:10.2218/resmedica.v22i1.811 Res Medica 2014, Volume 22, Issue 1 Williams, G. The New Dual Antiplatelet Therapy Agents and their Role in Acute Coronary Syndrome. Res Medica 2014, 22(1), pp.51-63. doi:10.2218/resmedica.v22i1.811 51 The New Dual Antiplatelet Therapy Agents and their Role in Acute Coronary Syndrome


Introduction
The long-term outcome of stent placement by percutaneous coronary interventions (PCI) for the management of acute coronary syndrome (ACS) is improved significantly by 2 key interventions: the use of high-pressure balloon inflations and the administration of periprocedural dual-antiplatelet therapy (DAPT).Although the benefits of DAPT as a medical treatment of ACS have been proven, its indication is obligatory in this setting to prevent post-stent placement complications, such as stent thrombosis and other ischaemic changes. 1 The basis of this strategy is the suppression of thromboxane A 2 production (by the administration of aspirin) and the addition of a P2Y 12 -receptor inhibitor, an agent that blocks adenosine diphosphate (ADP)-mediated platelet activation.For many years, the P2Y 12receptor inhibitor of choice has been the thienopyridine clopidogrel.Clopidogrel combined with aspirin for 12 months has widely become the standard practice following successful management of ACS with PCI. 2,3ere are, however, 2 concerns when using clopidogrel.The first is its delayed onset of action, which is due to the 2-stage activation process involving cytochrome P450 isoenzymes. 4 The second relates to the increasing evidence of a subset of patients that are clopidogrel hyporesponders or nonresponders, who are found to have delayed and/or insufficient inhibition of platelet function.The mechanism for this variable "clopidogrel resistance", also known as "high on-treatment platelet reactivity (HTPR)", is thought to be due to a number of genetic and non-genetic factors that affect the bioactivation of clopidogrel. 5,6An optimal inhibition of platelet function therefore cannot be guaranteed in these patients, especially in those who are carriers of the CYP2C19*2 loss-of-function polymorphism. 7This phenomenon has commonly been associated with disastrous and life-threatening sequelae, including stent thrombosis, recurrent myocardial infarction (MI), and cardiovascular death. 4Although relatively uncommon, this phenotype encompasses a group of patients whereby clopidogrel is not able to provide adequate platelet suppression and for whom alternative treatment options are required.
The goal of this article is to synthesize the most recent and relevant literature for the use of the antiplatelet agents prasugrel and ticagrelor in order to provide up-to-date clinical guidance of their use as alternatives for clopidogrel in patients who present with ACS undergoing PCI.

Methods
The articles cited in this paper were reviewed for their relevance to this topic.between the 2 treatment groups (0.3% vs 0.3%, p = 0.66). A number of non-haematological safety endpoints have been observed in ticagrelor, including higher rates of dyspnoea and ventricular pauses, and increased levels of creatinine and uric acid during treatment compared with clopidogrel.The exact mechanism for ticagrelor-related dyspnoea remains unproven, with no cardiac or pulmonary pathology observed. 16A number of observations from preliminary data have led to the hypothesis that adenosine may play a role in this presentation.Ticagrelor has been observed to inhibit adenosine uptake into erythrocytes by increasing circulating levels of adenosine with a theoretical effect similar to that of intravenous adenosine administration.8] In a study by Burki et al., 19 23 prasugrel has been taken up as the default P2Y 12 inhibitor in over half of the units providing PPCI services in the UK.
However, there have been doubts over this shift in clinical practice for a number of reasons.Firstly, there were criticisms of the primary efficacy endpoint used in the TRITON TIMI-38 being poorly defined. 24asugrel has been shown to significantly reduce the incidence of non-fatal MI when compared with clopidogrel (7.3% vs 9.5%, p < 0.001).However, when taking into account the rates of cardiovascular death between the 2 treatment groups, it was found to be 2.4% and 2.1% respectively (p = 0.31%).Also, the rate of both fatal and nonfatal stroke between the 2 groups were found to be 1.0% and 1.0% (p = 0.93).
While it cannot be disputed that there is a significant reduction in the incidence of stent thrombosis in patients receiving prasugrel compared with clopidogrel (1.1% vs 2.4% respectively, p < 0.0001), it may be argued that the reduction in non-fatal MI cannot justify the excess rates of fatal MI and severe bleeding incurred by this change.
Similarly, there is a perceived drive to prescribe ticagrelor for either PPCI or for all ACS patients in the wake of data procured from the PLATO trial, which is supported by recent NICE guidance. 25However, there are concerns raised over the data for ticagrelor therapy produced by this trial.
One that has already been discussed is the increased bleeding rate found in patients who did not undergo CABG when compared with the clopidogrel treatment regime, when applying either PLATO study bleeding definitions or TIMI major bleeding criteria (p = 0.03).Another refers to the PLATO PPCI subgroup analysis, 26 which found that the rate of primary endpoint was not found to be significantly different between the ticagrelor treatment group and the clopidogrel group, although there was a trend in favour of the former.There was also no significant difference found in mortality rates between the 2 treatment arms.
In light of this analysis, it appears that the evidence that has been presented for the benefit of ticagrelor over clopidogrel may not be as robust as initially thought.
Therefore, further clinical data may be required to assuage the concerns that have emerged over the replacement of clopidogrel with either prasugrel or ticagrelor.
A particular issue that has raised significant concerns as a result of the PLATO trial is the effect of geographical variation on the effectiveness of ticagrelor.It was noted that in North America, clopidogrel was associated with a better outcome trend than ticagrelor, whereas the reverse was true in the rest of the world (ROW), with a hazard ratio (HR) of 1.25 in North America compared with the HR of 0.84 overall. 27though the United States and the ROW displayed similar data quality and trial conduct, it was discovered that the median maintenance dose of aspirin, which was decided at the discretion of each centre, varied significantly between the 2 subgroups.
It was observed that on discharge, patients in North America were more likely to be receiving high-dose maintenance aspirin, whereas patients who were discharged from the ROW were more likely to be receiving low-dose maintenance aspirin.When analysed, this discrepancy may have accounted for between 80% to 100% of the There is currently no definitive biological explanation for this occurrence, although there are several potential hypotheses to explain why aspirin doses may modulate the efficacy of ticagrelor.Aspirin exerts an antithrombotic effect by the inhibition of platelet cyclooxygenase, which in turn reduces thromboxane A 2 release and additionally inhibits endothelial release of prostacyclin in a dose-dependent fashion at daily doses exceeding 80 mg. 29Prostacyclin reduces platelet reactivity and may synergistically contribute to the antiplatelet effects of P2Y 12 inhibitors in vivo, which results in the therapeutic effects of a higher mean level of P2Y 12 inhibition. 30The therapeutic effects of a higher mean level of P2Y 12 inhibition may be attenuated when endogenous prostacyclin production is inhibited.However, due to the absence of a clear pathological process, the possibility that this is the result of chance alone remains a reasonable consideration.

Learning Points
What is already known • The use of clopidogrel in conjunction with aspirin for patients with acute coronary syndromes (ACS) has come under scrutiny due to evidence of its varying levels of efficacy, with reports of severe and sometimes fatal outcomes.• Two novel antiplatelet agents, prasugrel and ticagrelor, have undergone large randomized trials to compare their efficacy to clopidogrel in the TRITON TIMI-38 and PLATO trials respectively.

What this study adds
• In an indirect comparison of the PLATO and TRITON TIMI-38 trials, ticagrelor is shown to have the greater overall clinical benefit with significantly reduced mortality.• The main indications for prasugrel use is for patients with acute STEMI, ACS patients with DM, and patients at high risk of stent thrombosis.• The main indications for ticagrelor use is for patients with NSTEMI, patients with a history of CKD, and in those where prasugrel is contraindicated.• Both agents have demonstrated a more consistent antiplatelet effect than clopidogrel and have shown to be effective alternatives for patients who are nonresponsive to clopidogrel therapy.
observed regional interaction.A similar geographical trend in high maintenance dose of aspirin was observed in the TRITON-TIMI 38 trial, with 66% of patients in North America receiving high-dose aspirin compared with only 28% in the ROW, with an odds ratio of 5.19 (95% CI: 4.72-5.70;p < 0.001). 28Despite this significant difference between the 2 subgroups, there was no modification of the clinical effect of prasugrel versus clopidogrel based on discharge aspirin dose with respect to the primary efficacy endpoint (HR CVD/MI/stroke = 0.78 [95% CI: 0.64%-0.95%]for aspirin < 150 mg; HR CVD/MI/stroke = 0.87 [95% CI: 0.69-1.10]for aspirin > 150 mg; p = 0.48).
However, there is a possible trend observed in high-dose maintenance aspirin with poorer clinical outcomes when given with ticagrelor.Therefore, in conjunction with the results from this analysis and current guideline recommendations, the use of lowdose maintenance aspirin is likely to be associated with the most favourable outcomes with ticagrelor administration.A final consideration in this article is the comparison between prasugrel and ticagrelor as to which is the most effective antiplatelet agent.Currently, there is no trial that directly compares the 2 agents for the management of ACS patients, which makes much of the potential differences between the two unresolved.Additionally, due to the varying study designs of the TRITON TIMI-38 and PLATO trials, it is not possible to extrapolate the results for a definitive comparison.Despite these limitations, there are a number of simple comparisons between prasugrel and ticagrelor which can be drawn from these 2 studies.Firstly, while the benefit of prasugrel in the TRITON TIMI-38 trial was exclusively attributed to the reduced rate of non-fatal MI of 89 patients, ticagrelor's reduction on mortality in PLATO of 107 deaths clearly represents a major clinical outcome difference between the 2 trials.As previously discussed, both prasugrel and ticagrelor have been shown to significantly reduce the incidence of stent thrombosis compared with clopidogrel.The number needed to treat (NNT) for prasugrel was calculated to be 77 for preventing stent thrombosis, whereas the NNT for ticagrelor was 143.These results may therefore advocate the use of prasugrel over ticagrelor in patients with a higher risk of developing stent thrombosis (e.g.those with diabetes mellitus (DM) and small stent diameter).Another important consideration is that while both medicines lowered the rate of the primary and secondary endpoints in patients with DM compared with clopidogrel, the NNT for DM patients taking prasugrel was 21 compared with 48 for ticagrelor.One may therefore favour the use of prasugrel over ticagrelor for patients with DM who present with ACS and are intended for PCI.With regard to the different ACS subsets, there seems to be a significant benefit for the use of prasugrel rather than ticagrelor in STEMI patients (NNT 42 vs 71 respectively).On the other hand, ticagrelor was shown to reduce the primary endpoint for NSTEMI patients, but not for those with unstable angina, whereas prasugrel had an effect on both.This reduction in mortality may favour prasugrel administration for patients who present with STEMI and ticagrelor for NSTEMI patients.In terms of side effects, both therapies have been found to similarly increase the risk of non-CABG-related TIMI major bleeding events compared with clopidogrel.However, CABG-related TIMI major bleedings were significantly more prevalent in prasugrel than ticagrelor.In addition, patients who have high risk characteristics where prasugrel is contraindicated, such as a history of transient ischaemic attack (TIA) or stroke, age > 75 years, body weight of < 60 kg, ticagrelor therapy may be more suitable.As discussed above, the side effects of ticagrelor administration of dyspnoea and ventricular pauses, which are seldom seen in prasugrel administration, may be a cause for concern in terms of drug discontinuation, along with the fact that ticagrelor is administered twice daily as opposed to once daily in the case of prasugrel.Additionally, there are concerns over the increased rate of cancer, especially in women, with prasugrel therapy in TRITON TIMI-38 compared with clopidogrel.In a review of the TRITON TIMI-38 trial by Floyd JS et al., 31 it was found that 92 patients had new solid tumours in the prasugrel treatment arm (1.4%) as opposed to 64 in the clopidogrel arm (0.9%) with a HR of new and worse solid cancers of 1.44 (p = 0.02).Currently, the underlying mechanism of this trend is unclear and no association has previously been made between other antiplatelet drugs such as aspirin, clopidogrel, and ticagrelor with an increased risk of new or worsening neoplasms.However, this matter is worth noting when considering the long-term use of prasugrel, and further research must be undertaken.In short, the main indications for the use of prasugrel based on current understanding are patients presenting with acute STEMI referred for primary PCI, ACS patients with DM, or those who have a high risk of stent thrombosis.Ticagrelor, on the other hand, may provide optimal benefit for patients with NSTEMI treated with conservative or invasive therapy, those with previous TIA or stroke, advanced age, or small body surface.Additionally, by indirectly comparing the PLATO and TRITON TIMI-38 trials, one may infer the superiority of ticagrelor to prasugrel for chronic preventative use when taking into account its absolute mortality reduction, reduced haemorrhagic fatalities, and less CABG-related bleeding, as well as a lack of cancer risk.This may therefore that the optimal treatment regimen would be prasugrel prescribed for the first 30 days due to its clear clinical benefit in the early stages of treatment, and then switched to ticagrelor after 30 days due to its potential superiority in achieving favourable longterm outcomes.However, further study is needed in order to ascertain whether this tandem strategy of prasugrel and ticagrelor would be safe and effective in providing an overall clinical benefit in comparison to each medication on its own.Conclusion Prasugrel and ticagrelor have been shown to be adequate P2Y 12 antiplatelet therapy alternatives to clopidogrel in the management of patients with ACS.The results of the TRITON TIMI-38 and PLATO trials have provided a significant insight into the benefits and drawbacks of the use of both agents.While prasugrel and ticagrelor have both been shown to clinically improve platelet inhibition and significantly reduce the incidence of stent thrombosis compared with clopidogrel therapy, both increase the risk of significant bleeding incidents.This is particularly the case in patients with risk factors such as low body weight, advanced age (>75 years old), or those that are due to undergo CABG.There are certain subgroups of ACS patients that have been especially shown to benefit from these new agents.Prasugrel has been shown to improve clinical outcomes in diabetic ACS patients compared with non-diabetic ACS patients, and ticagrelor has demonstrated beneficial outcomes for ACS patients who are due to undergo CABG or have a history of CKD.There are some doubts over the data from both trials which suggest that prasugrel and ticagrelor are overall superior treatments to clopidogrel, hence further study is required to confirm this.However, there are a number of limitations with clopidogrel use that both of these new agents are not susceptible to, such as a delayed onset of action and a wide variability in efficacy.Both ticagrelor and prasugrel have been shown to be appropriate and effective treatment alternatives for ACS patients who display clopidogrel treatment resistance or failure.