Introduction
Antiplatelet therapy is a cornerstone in coronary artery disease (CAD) management. Acetylsalicyclic acid (ASA) has been known for many decades to have antithrombotic efficacy. Already in the 1980’s, the ISIS-2 study demonstrated that ASA reduces mortality in acute myocardial infarction (AMI) by 23 %.1 ASA leads to irreversible inactivation of cyclooxygenase 1 and thereby blocks the formation of thromboxane A2, a potent mediator of platelet aggregation. Nevertheless, ASA is a relatively weak antiplatelet agent and only inhibits one of many pathways leading to platelet activation. Patients with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) remained at a substantial risk of future ischaemic events, despite the treatment with ASA.2 Only the combination of ASA with an additional antiplatelet agent could reduce the rate of cardiovascular events.3 In the 1990’s thienopyridines were introduced. Ticlopidine and clopidogrel inhibit platelet activation by blocking the adenosine diphosphate (ADP) P2Y12 pathway. Ticlopidine, the first generation thienopyridine, was effective in reducing ischaemic events, but was associated with serious haematological toxicity. Clopidogrel, the second generation thienopyridine, replaced ticlopidine owing to its equivalent efficacy and lower haematological toxicity. During the last two decades, the utility of clopidogrel has been evaluated in several common clinical scenarios in a large number of patients. The benefits of clopidogrel in patients with stable CAD undergoing elective PCI and in patients presenting with ACS are well established.4–6 However, there are several limitations of clopidogrel, including delayed onset of action and substantial interpatient variability in platelet inhibition.7,8
Prasugrel
Prasugrel is a third-generation thienopyridine, and like clopidogel is a prodrug and binds irreversibly at the P2Y12 receptor. However, it exhibits a few advantages over clopidogrel – a more rapid and stronger antiplatelet effect and a very low rate of non-responders. Furthermore, genetic polymorphism of cytochrome P450 do not have an impact on the efficacy of prasugrel.9 After a 60 mg loading dose prasugrel reaches maximal plasma concentration at 30 min.10 In contrast, clopidogrel has a much longer onset of action at two hours after administration of the loading dose. The active metabolite of prasugrel has an elimination half-life of ≈7 hours. Among patients undergoing PCI, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600 mg clopidogrel loading dose. Furthermore, a maintenance prasugrel dose of 10 mg/day results in a more potent and consistent inhibition of platelet activation than the standard clopidogrel maintenance doses of 75 or 150 mg/day. The Trial to assess improvement in therapeutic outcomes by optimising platelet inhibition with prasugrel – thrombolysis in myocardial infarction (TRITON–TIMI) 38 trial included more than 13,000 ACS patients with known coronary anatomy. Planned PCI also showed that prasugrel (60 mg loading dose followed by a 10 mg/day maintenance dose) compared with clopidogrel (300 mg loading dose and a 75 mg/day maintenance dose) significantly reduced the combined primary endpoint of cardiovascular death, non-fatal myocardial infraction (MI) and non-fatal stroke (9.9 vs 12.1 %; HR=0.81; P<0.001).11 Rates of cardiovascular death (2.1 % vs 2.4 %; HR=0.89; P=0.31) were not reduced by prasugrel relative to clopidogrel, whereas rates of stent thrombosis were significantly lower (1.1 % to 2.4 %; HR=0.48; P<0.001)in the prasugrel-group. The diabetic subgroup (especially those with insulin dependent diabetes) had particular benefit from the prasugrel treatment. The relative risk reduction was 26 % in comparison to 8 % among non-diabetics. Unfortunately, this beneficial effect was accompanied by an increase of life-threatening bleeding complications (1.4 % vs 0.9 %; HR=1.52; P=0.01). Furthermore, among elderly and patients with a body weight of less than 60 kg no net clinical benefit was observed. Patients who had had a prior cerebrovascular event even had worse clinical outcomes. As a consequence, prasugrel is contraindicated in patients with prior stroke/transient ischemic attack (TIA). Its use is generally not recommended in patients aged ≥75 years or in patients with lower body weight (<60 kg). A reduced maintenance dose of 5 mg can be considered in these patients, but outcome data are not available with this dose. Although prasugrel markedly reduced ischaemic events after PCI for ACS, a major criticism of the TRITON–TIMI 38 trial was that the clopidogrel group received a 300 mg instead of a more effective 600 mg loading dose.
In the Testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel (TRIGGER-PCI) study, the efficacy of prasugrel vs clopidogrel in patients with high on-treatment platelet reactivity after elective PCI was evaluated.12 No benefit was observed with prasugrel. Prasugrel is approved in combination with ASA in ACS with or without ST elevation patients with known coronary anatomy who are planned for PCI.
Ticagrelor
Ticagrelor is not a thienopyridine, but binds also reversibly at the ADP P2Y12 receptor.9Ticagrelor is administered orally in its active form and does not need the metabolic activation required with thienopyridines. Similar to prasugrel, ticagrelor provides faster, more intense and more consistent platelet inhibition than clopidogrel. Its bioavailability seems to be less affected by genetic factors. Ticagrelor is rapidly absorbed with a maximum plasma concentration at 1.5 hours. Due to its shorter half-life, plasma levels are maintained for only 12 hours, making a twice-a-day regimen necessary (2 x 90 mg/day). This might be beneficial in bleeding complications or planned operations like coronary artery bypass graft (CABG) surgery, but it may pose a problem for noncompliant patients. However, the ONSET/OFFSET study demonstrated that the platelet inhibition 24 hours after the last dose was equivalent in ticagrelor- and clopidogrel-treated patients.13 These data suggest that patients who miss one dose of ticagrelor and patients with maintenance clopidogrel therapy will have similar platelet inhibition at 24 hours. Ticagrelor (180 mg loading dose and a 2 x 90 mg/day maintenance dose) was compared with clopidogrel (300 mg loading dose and a 75 mg/day maintenance dose, in case of PCI additional loading with 300 mg) in the Platelet inhibition and patient outcomes (PLATO) study in patients with ACS.14 In contrast to the TRITON TIMI 38 trial, ACS-patients were included regardless of the initial treatment strategy (medically or invasive). Furthermore, inclusion of patients pretreated with clopidogrel was allowed.
In the PLATO study, ticagrelor significantly reduced the combined primary endpoint of cardiovascular mortality, MI and stroke (9.8 % vs 11.7 %; HR=0.84; P<0.001) without increasing the risk of major bleeding. There were also reductions in cardiovascular, total mortality and stent thrombosis with ticagrelor. Ticagrelor has been associated with side effects such as bradycardia and dyspnoea, most likely related to blockage of adenosine reuptake. It usually occurs early in the course of treatment and in most cases is self-limited. Ticagrelor is approved in combination with ASA in non-ST or ST elevation ACS patients who are treated with either PCI, bypass surgery or medically. In patients with haemorrhagic stroke or patients taking medications that are strong CYP3A4 inhibitors or inducers ticagrelor is contraindicated.
A major criticism of the PLATO trial was that a significant interaction between treatment effect and geographic region was seen, with an apparently smaller ticagrelor effect in North America than in other regions (e.g. East Europe). In an analysis by Mahaffey et al. a significantly higher proportion of patients in North America receiving higher ASA maintenance dose (≥300 mg/day) was identified as a possible explanation for the regional difference.15 There is no clinical data on the efficacy of ticagrelor in setting of PCI in stable CAD.
Vorapaxar
Vorapaxar is an oral competitive protease-activated–receptor 1 (PAR- 1) antagonist that inhibits thrombin-induced platelet aggregation. In the Thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRACER) trial, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point (18.5 vs 19.9 %; HR=0.92; P=0.07) among patients with in non-ST elevation ACS.16 However, vorapaxar significantly increased the risk of moderate and severe bleeding (7.2 vs 5.2 %; HR=1.35; P<0.001), including intracranial haemorrhage (ICH) (1.1 vs 0.2 %; HR=6.45; P<0.001).
The Thrombin receptor antagonist in secondary prevention of atherothrombotic ischaemic events (TRA 2P) – Thrombolysis in myocardial infarction (TIMI) 50 trial was designed to evaluate the efficacy and safety of vorapaxar in reducing atherothrombotic events in patients with stable atherosclerosis treated with standard therapy.17 TRA 2P-TIMI 50 showed that vorapaxar was associated with a reduction in the composite end point of cardiovascular death, MI or stroke (9.3 vs 10.5 %; HR=0.87; P<0.001). A benefit was most apparent in patients with a history of MI and no history of stroke/transient ischaemic attack (TIA) who weighed more than 60 kg. However, vorapaxar was also associated with increased rates of moderate and severe bleeding (4.2 vs 2.5 %; HR=1.66; P<0.001), including ICH, with the latter occurring most frequently in patients with a history of stroke. On May 5, 2014, vorapaxar has received its first global approval in the USA for secondary prevention of atherothrombotic events in patients with previous MI and peripheral arterial disease. Vorapaxar must not be used in patients who have had a stroke, TIA, or ICH.
Optimum Antiplatelet Therapy in ST Elevation Myocardial Infarction (STEMI)
Patients with STEMI and planned primary PCI require particularly urgent platelet inhibition and represent a group potentially benefiting most from the new antiplatelet therapies.
In the STEMI cohort of the TRITON-TIMI 38 trial prasugrel significantly reduced the primary endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke by 32 % after 30 days (6.5 vs 9.5 %, P=0.0017).18 The absolute risk reduction was 3.0 %. In particular, benefits were seen among patients with anterior STEMI. In comparison to clopidogrel prasugrel reduced the primary endpoint in these patients by 43 % – regardless of a concomitant use of glycoprotein IIb/IIIa blockers. The rate of bleeding complications not related to CABG was similar in the prasugrel- and clopidogrel-group (2.4 vs 2.1 %). However, in patients with bypass surgery TIMI major bleedings occurred more often among those with prasugrel therapy (18.8 vs 2.7 %). In general, the rate of bleeding complications in the STEMI cohort was not increased – despite a use of glycoprotein IIb/IIIa blockers in 60 % of the patients.
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In the STEMI cohort of the PLATO trial ticagrelor reduced the primary endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke by 13 % (9.4 vs 10.8 %; P=0.07).19 The absolute risk reduction was 1.4 %. Ticagrelor also reduced several secondary end points, such as MI (HR=0.80; P=0.03), mortality (HR=0.82; P=0.05) and stent thrombosis (HR, 0.66; P=0.03). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76).
In the Rapid activity of platelet inhibitor drugs primary PCI (RAPID) study pharmacodynamic measurements after administration of prasugrel and ticagrelor loading dose were performed.20 In terms of residual platelet reactivity there were no significant differences after two and four hours between the two agents. Surprisingly, four hours were required to achieve sufficient platelet inhibition in the majority of STEMI patients. Futhermore, morphine use was associated with a delayed activity of prasugrel and ticagrelor.
Interestingly, the guidelines of the European Society of Cardiology (ESC) and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) do not completely agree on the utilisation of novel antiplatelet agents (see Table 1). The STEMI guidelines of the ESC give ticagrelor and prasugrel a IB recommendation.21 However, prasugrel should only be given in clopidogrel-naive patients, if there is no history of prior stroke/TIA and age <75 years. In general, these two novel antiplatelet agents are preferred over clopidogrel. According to the ESC guidelines clopidogrel should only be used (IC recommendation) when prasugrel or ticagrelor are either not available or contraindicated. On contrary, the ACCF/AHA STEMI guidelines do not declare superiority of ticagrelor and prasugrel over clopidogrel.22 All three agents are given a IB recommendation. In the eyes of the American task force an important shortcoming of the prasugrel and ticagrelor data is that there are no specifically designed STEMI trials and only post-hoc secondary analyses exist.
In summary, prasugrel may be best suited for younger STEMI patients with large areas of myocardium at risk (e.g. anterior STEMI) or diabetes who are not planned for CABG and have a low risk of bleeding. Ticagrelor may be the best option for older patients or patients with a moderate bleeding risk and patients with a conservative strategy. Clopidogrel may rather be used in patients with a contraindication for prasugrel and ticagrelor or concomitant chronic anticoagulation therapy.
Optimum Antiplatelet Therapy in Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS)
Patients with NSTE-ACS are at high risk for major adverse events and do also benefit from the new antiplatelet agents. However, NSTEACS patients tend to be older and have more co-morbidities such as chronic renal failure, and therefore there is an increased risk for bleeding complications.
In the NSTE-ACS cohort of the TRITON-TIMI 38 trial prasugrel significantly reduced the primary endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke (HR=0.82, P=0.002), but was accompanied by an increase in the rate of major bleeding complications (HR 1.40, P=0.02).23 However, in patients who met the criteria for prasugrel use recommended by the European Medicines Agency (EMEA), thus excluding patients from the analysis with prior TIA/stroke, with weight <60 kg or age ≥75 years, prasugrel was superior with regards to ischaemic events without significant differences in non-CABG major bleedings. Most recently, the Comparison of prasugrel at the time of PCI or as pretreatment at the time of diagnosis in patients with non- ST elevation myocardial infarction (NSTEMI) (ACCOAST) trial has been published.24 Over 4,000 NSTEMI patients who were scheduled to undergo coronary catheterisation within 48 hours were included in this study. Patients were randomised to prasugrel (30 mg loading dose) or placebo before coronary angiography. When PCI was indicated, an additional loading dose of 30 mg prasugrel was given in the pretreatment group and a 60 mg loading dose was given in the control group. Pretreatment with prasugrel before angiography did not reduce ischaemic events (10.0 versus 9.8 %, HR=1.02; P=0.81), but was associated with more TIMI major bleeding (2.6 vs 1.4 %, HR=1.90, P=0.006).
The Targeted platelet inhibition to clarify the optimal Strategy to medically managed acute coronary syndromes (TRILOGY-ACS) is also a recent study which examined the effect of prasugrel in patients not undergoing revascularisation.25 Patients were randomised in the study only after a decision for medical management without revascularisation was made. At a median follow-up of 17 months Prasugrel did not significantly reduce the primary endpoint in comparison to clopidogrel (13.9 vs 16.0 %, HR=0.91; P=0.21). The results of TRILOGY-ACS do not support extending the indication for prasugrel to medically managed patients with NSTE-ACS.
There is also a post-hoc secondary analysis of the NSTE-ACS PLATO cohort. Consistent with the results in the overall population ticagrelor significantly reduced the primary endpoint (10.0 vs 12.3 %; HR=0.83; P=0.0013), cardiovascular (3.7 vs 4.9 %; HR=0.77; P=0.0.007) and total mortality (4.3 versus 5.8 %; HR=0.76; P=0.002) in patient with and without revascularisation.24 Major bleeding rate did not differ between the two treatment groups (13.4 vs 12.6 %; HR=1.07; P=0.26), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs 3.8 %; HR=1.28; P=0.0139).
There is no randomised comparison of prasugrel vs ticagrelor. However, Biondi-Zoccai et al. conducted an adjusteded indirect meta-analysis comparing both agents in patients with ACS.27 Head-to-head comparison suggested similar efficacy of prasugrel and ticagrelor, but prasugrel appeared to be more benefical with regard to the occurrence of stent thrombosis, while increasing the risk of bleeding complications.
There are two important advantages of ticagrelor over prasugrel in the setting of NSTE-ACS. First, according to the ESC guidelines a P2Y12 inhibitor should be added to ASA as soon as possible,26 and ticagrelor can be given without knowledge of the coronary status. In the ACCOAST trial administration of prasugrel before coronary angiography was not associated with a net clinical benefit. Secondly, ticagrelor also improves prognosis in medically managed patients.26
The current NSTE-ACS guidelines of the ESC prefer ticagrelor and prasugrel over clopidogrel28 (see Table 2). Clopidogrel is only recommended for patients who cannot receive ticagrelor or prasugrel (IA recommendation). In contrast to the European guidelines the ACCF/AHA NSTE-ACS guidelines do not endorse prasugrel or ticagrelor over clopidogrel.29
There is only little data on the use of the novel antiplatelet agents in daily clinical practice. Randomised clinical trials usually enroll selected patient populations that may not be representative for patients seen in everyday practice. In an analysis of the Greek Antiplatelet registry (GRAPE) registry 24.1 % and 37.2 % of the patients with ACS undergoing PCI received prasugrel and ticagrelor, respectively.30 However, solid data is lacking, whether the novel antiplatelet agents also improve prognosis in an all-comer population.
In summary, ticagrelor may be the best option for most patients with NSTE-ACS, in particular in patients managed conservatively. Prasugrel may be best suited for younger patients with scheduled PCI and large areas of myocardium at risk or diabetes mellitus who have a low risk of bleeding. Again, clopidogrel should rather be used in patients with a contraindication for prasugrel and ticagrelor or concomitant chronic anticoagulation therapy.
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Conclusions
The two novel antiplatelet agents prasugrel and ticagrelor provide better platelet inhibition than clopidogrel. These drugs were shown to be more effective than clopidogrel in most subsets of patients with ACS, but were associated with more bleeding complications. Careful patient selection and balancing the benefits and risks optimises the selection of prasugrel, ticagrelor and clopidogrel in ACS. Vorapaxar may be a good option for secondary prevention in patients with stable atherosclerosis and no history of stroke, TIA, or ICH.