Cardiovascular (CV) events are a major cause of mortality worldwide1 that are often precipitated by acute coronary syndromes (ACS). ACS result from the acute obstruction of coronary arteries and are defined as either unstable angina (UA) or myocardial infarction (MI), with or without ST-segment-elevation (STEMI and NSTEMI, respectively). Patients with moderate- to high-risk ACS are managed by an early invasive approach that includes coronary angiography followed by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). There is a high inherent risk of thrombotic complications with ACS or with the use of PCI, while MI and stroke may be serious complications of CABG surgery. Platelet aggregation and activation play key pathophysiological roles in the atherothrombotic process and the consequent development of CV events. In patients with ACS and those undergoing PCI, the risk of peri-interventional and long-term cardiac complications, including death and MI, may be reduced by utilising anticoagulant and/or antiplatelet therapies.2
The impact of oral antiplatelet medications on the prevention and treatment of CV events is well-established, with aspirin and the once-daily- administered thienopyridine clopidogrel being the cornerstones of antithrombotic therapy in patients with ACS.3,4 Both aspirin and clopidogrel exert their beneficial antiplatelet effects by inhibiting platelet aggregation and activation. Aspirin irreversibly binds to the cyclo-oxygenase 1 (COX-1) receptor to inhibit the formation of thromboxane A2, thereby inhibiting platelet activation and aggregation, while clopidogrel irreversibly and selectively blocks adenosine diphosphate (ADP)-dependent platelet activation and aggregation via blockade of the P2Y12 receptor.5 Dual therapy with aspirin plus clopidogrel is generally considered by cardiologists to be a gold standard treatment for patients with UA/NSTEMI ACS, for those with STEMI ACS and for those undergoing PCI. This therapeutic strategy can offer up to a 20% additional reduction in death, non-fatal MI and stroke over aspirin monotherapy.6
Despite the proven efficacy of aspirin and clopidogrel in patients with ACS and those undergoing PCI, CV events remain an important cause of morbidity and mortality. The challenges of oral antiplatelet therapy in these patients are further highlighted by the results of recent clinical trials, as discussed later. Since antiplatelet agents block pathways that are important to thrombosis as well as haemostasis, their use may be associated with a high bleeding risk.
A major challenge, therefore, is to find the optimal level of platelet inhibition that is needed to obtain a balance between the prevention of ischaemic events and minimisation of the risk of bleeding in various clinical settings. Determination of this ideal level will help optimise the balance between safety and efficacy. It should be noted that this challenge also gives rise to a further set of other challenges, such as the need to identify optimal dose and timing of therapy, since these factors strongly influence platelet inhibition.
Challenges with the Thienopyridine Clopidogrel
Some of the pharmacodynamic and pharmacokinetic properties of clopidogrel give rise to pharmacological limitations, including both delayed onset and offset of action and large inter-individual variability in platelet response.
Delayed Onset and Offset of Action
In the acute setting, such as in patients with STEMI or NSTEMI scheduled to undergo PCI, antiplatelet therapy needs to be given as early as possible. Cardiologists therefore require antiplatelets that have a rapid onset of action. However, clopidogrel has a delayed onset of action, which is largely attributed to the two-step CYP450 isoenzyme-dependent hepatic metabolisation of the prodrug into the active metabolite.7,8 The clinical impact of this slow onset of action is that in patients requiring an immediate antiplatelet effect, treatment with clopidogrel (300mg loading dose) needs to be initiated at least six hours prior to the intervention in order to achieve a meaningful preventative benefit in terms of reduction in the risk of death, MI or urgent vessel revascularisation.2,9
A loading dose of clopidogrel (generally 300 or 600mg) is usually administered to achieve faster platelet inhibition, with maintenance doses subsequently administered to sustain the level of inhibition. However, the optimal loading dose needs to be identified. While a 300mg loading dose of clopidogrel is the current standard, a 600mg dose is becoming increasingly used after clinical studies that showed its superiority over the lower dose.
An example was the ALBION study, which was a randomised, multicentre, open-label trial that evaluated the efficacy of different loading doses of clopidogrel in NSTEMI patients undergoing PCI.10 The results showed the 600mg loading dose to achieve a faster and more potent inhibition of platelet aggregation (IPA) than a 300mg dose (p<0.05). However, the 900mg dose was not superior to the 600mg dose. This was consistent with a study by von Beckerath, where there was no major difference in the impact of the two loading doses of clopidogrel (600 and 900mg) on platelet inhibition.11 The recent double-blind, randomised CURRENT-OASIS 7 trial compared different clopidogrel loading doses in patients with ACS or STEMI managed with an early invasive strategy (n=25,087);12 it should be noted that all patients were given either a high or low dose of aspirin. The results of a subgroup analysis suggested the 600mg loading dose to be superior to the 300mg loading dose. However, the findings of this analysis should be treated with caution as the primary end-point (a composite of death/MI/stroke at 30 days) was not achieved in the CURRENT-OASIS 7 trial.
Another challenge with the use of clopidogrel is its delayed offset of action. Clopidogrel binds irreversibly to P2Y12 platelet receptors, resulting in the platelets being inactivated for the remainder of their lifespan (seven to 10 days). The offset of action therefore depends on the presence of new platelets in the circulation in the absence of active drug, and can take around five days in the absence of treatment. The delayed offset of action of clopidogrel has an impact on the timing of drug administration, as dosing needs to be stopped five days prior to the surgical intervention in order to restore normal haemostasis. However, stopping clopidogrel therapy so early on may increase the risk of thrombotic events before or during the surgery. On the other hand, if clopidogrel administration is not stopped five days prior to the surgery, there may be a risk of increased bleeding and associated complications. There are numerous reports that indicate an increased risk of major bleeding, transfusion requirements, chest output and/or re-exploration in patients who discontinued clopidogrel too soon prior to surgery.13–24 The limitations of clopidogrel, such as the delayed onset and offset of action, mean that it can only be administered during a certain period before the intervention, as the wrong timing may result in an imbalance of the prevention of thrombotic complications and minimisation of the bleeding risk.
Inter-patient Variability in Platelet Inhibition and Antiplatelet Response
An important issue with clopidogrel therapy is the presence of large variability in the platelet response (i.e. IPA) in different patients with ACS.25–30 This clopidogrel hypo-/non-responsiveness may have clinical implications. For instance, a systematic review that included data from 3,688 clopidogrel-treated patients who underwent PCI showed clopidogrel non-responsiveness to be associated with an increased risk of adverse CV outcomes.31 The mechanisms leading to the poor platelet inhibition and response are not very well understood, but are likely to be multifactorial (see Figure 1).25 An important factor may be the presence of clopidogrel resistance as there are several reports linking CYP450 activity to the variability of response.8,32–34 In particular, nearly 25% of clopidogrel-treated patients carry a variant allele of the gene that encodes the CYP2C19 enzyme.35,36 Subjects carrying this allele form none or little of the active metabolite of clopidogrel. This clopidogrel resistance may play a large role in the lack of platelet inhibition and, consequently, clopidogrel hyporesponsiveness.35,36
One strategy to overcome clopidogrel hyporesponsiveness is to utilise a higher loading dose as this could produce faster and more potent platelet inhibition. The concept of using a loading dose has been previously described in this article. Briefly, a 600mg dose is as safe as the 300mg dose but offers improved IPA and lower 30-day CV event rates.37 However, it should be noted that while the 600mg loading dose may reduce clopidogrel hyporesponsiveness,38 it has not been shown to moderate the wide variation in response to clopidogrel.39,40 Similarly, increasing the maintenance clopidogrel dose from 75 to 150mg has been shown to reduce but not eliminate hyporesponsiveness.41,42 Therefore, there is a need to determine the optimal loading and maintenance doses of clopidogrel and whether increasing the dose can reduce or eliminate the variability in response. Duration of the dose is also known to influence the responsiveness, as hyporesponsiveness has been shown to decrease with increasing treatment duration.27,43–45
Development of New Oral Antiplatelet Agents
The pharmacological limitations of clopidogrel have prompted the development of new oral antiplatelet agents with the aim of improving the rate of onset and offset of action as well as improving the consistency of platelet inhibition. The new oral antiplatelet drugs are the recently approved prasugrel and ticagrelor, which is in late stage clinical development.
Prasugrel, a thienopyridine administered once daily, was approved in Europe and the US in 2009 for the reduction of risk of thrombotic CV events in patients with ACS undergoing PCI. PRINCIPLE-TIMI 44, a randomised, double-blind, cross-over trial, compared prasugrel (60mg loading dose followed by 10mg/day maintenance dose) with clopidogrel (600mg loading dose followed by 150mg/day maintenance dose); it should be noted that all patients also received aspirin. The results of this study showed the loading dose (60mg) of prasugrel to result in a significantly faster, greater and more consistent inhibition of platelet aggregation than the loading dose (600mg) of clopidogrel in patients undergoing cardiac catheterisation for planned PCI (see Figure 2; p<0.0001).46 The greater potency and speed of action may be partly attributed to the more efficient absorption of prasugrel and its rapid conversion to the active metabolite, since the prodrug requires only one CYP450-dependent metabolisation step.7,47–49 The greater consistency of platelet inhibition may be largely attributed to the more efficient formation of the active metabolite as prasugrel has a much lower genetically determined resistance than clopidogrel.50,51 Despite these benefits, prasugrel has one pharmacological limitation when used pre-operatively: it cannot overcome the delayed offset of action problem because, similar to clopidogrel, prasugrel also binds irreversibly to the P2Y12 receptor.
The randomised, double-blind TRITON-TIMI 38 phase II trial compared the clinical safety and efficacy of prasugrel (60mg loading dose followed by 10mg daily maintenance dose) with that of clopidogrel (600mg loading dose followed by 75mg daily maintenance dose) in moderate- to high-risk ACS patients undergoing scheduled PCI.52 At 15-month follow-up, the primary end-point (composite of CV death, non-fatal MI or non-fatal stroke) was achieved in a significantly lower proportion of patients in the prasugrel group versus the clopidogrel group (9.9 versus 12.1%; p<0.001).52,53
The superior efficacy of prasugrel over clopidogrel was noticeable during the first three days of treatment and was still apparent at the end of the study.54 These results indicate that the efficacy of both the loading and the maintenance doses of prasugrel was superior to that of the relevant doses of clopidogrel. They also emphasise the importance of maintaining high levels of inhibition of platelet aggregation via P2Y12 receptor inhibition, not only for the prevention of peri-procedural ischaemic events but also during long-term follow-up. Finally, in the TRITON-TIMI 38 study, the rates of definite/probable stent thrombosis were significantly lower with prasugrel versus clopidogrel (1.13 versus 2.35%; p<0.0001).53 Prasugrel therefore may be effective in long-term treatment after stent implantation. Further studies are needed to evaluate the optimal duration of prasugrel-based dual therapy.
Prasugrel may be more suitable than clopidogrel for patient subsets. For instance, a TRITON-TIMI 44 sub-analysis of patients with STEMI who underwent either primary or secondary PCI showed the primary end-point to be reached significantly more frequently in prasugrel-treated patients than in clopidogrel-treated patients (p=0.022). There was a similar rate of non-CABG-related TIMI major or minor bleeding in the two groups.55 Prasugrel may be especially useful in patients with diabetes who are predisposed to a prothrombotic risk. It has been shown that prasugrel induced a larger net clinical benefit in patients with diabetes (p=0.001) than in those without diabetes (p=0.16) compared with clopidogrel-treated patients.56 Furthermore, there were similar rates of TIMI major haemorrhage and TIMI major or minor bleeding in prasugrel- and clopidogrel-treated diabetic patient groups.
Results from the safety cohort of the TRITON-TIMI 38 study showed that the incidence of TIMI major bleeding was significantly greater in patients receiving prasugrel than in those receiving clopidogrel (2.4 versus 1.8%; p=0.03).52 Similarly, the incidence of life-threatening bleeding (1.4 versus 0.9%; p=0.01), including non-fatal bleeding (1.1 versus 0.9%; p=0.23) and fatal bleeding (0.4 versus 0.1%; p=0.002), was also higher in prasugrel-treated patients.52 Furthermore, according to post hoc exploratory analyses, in patients with a prior stroke or transient ischaemic attack, those 75 years of age or older and patients weighing less than 60kg, there was a higher bleeding risk and little net clinical benefit of prasugrel over clopidogrel (see Table 1).52 It has been suggested that in these patients either prasugrel should not be given or a lower maintenance dose should be utilised in order to reduce the bleeding risk.
This lower dose is currently being investigated in the randomised, double-blind TRILOGY-ACS phase III trial, with an estimated accrual of 10,300 medically managed patients with UA/NSTEMI ACS. The primary outcome measure of the study is the reduction in risk of the composite end-point of first occurrence of CV death, MI or stroke. Future studies need to investigate the optimal dose of prasugrel in these patients. Since the above-mentioned post hoc analysis linked prasugrel with increased intracranial haemorrhage, prasugrel is contraindicated in patients with a history of cerebrovascular disease. Finally, study evidence indicates that prasugrel therapy should not be started in patients with ACS who are expected to undergo CABG surgery since the drug has been associated with an increased risk of major bleeding (p<0.001).52 The results of the TRITON-TIMI 38 study emphasise the importance of balancing a reduction in thrombotic risk with minimisation of bleeding risk, and also indicate the need to consider the bleeding risk/efficacy ratio with prasugrel in patients with ACS.
Ticagrelor is the first reversible, direct-acting, twice-daily-administered oral P2Y12 antagonist and is currently in late-stage clinical development. It belongs to a new chemical class of antiplatelet agents: the cyclopentyl-triazolo-pyrimidines.57 Ticagrelor differs from the thienopyridines in that it acts directly on the P2Y12 receptor and does not require metabolic activation, and therefore has the potential for faster platelet inhibition. Ticagrelor can almost completely inhibit platelet aggregation after just two hours from initial drug administration.57 Furthermore, ticagrelor offers a greater plateau level of platelet aggregation compared with clopidogrel (90–95 versus 60%).57,58 Ticagrelor also differs from thienopyridines in that it has a low affinity for the P2Y12 receptor and can bind to it irreversibly, and therefore it possibly provides a shorter offset of action.58
The safety and efficacy of ticagrelor have been investigated in the phase II DISPERSE-2 trial and the phase III PLATO trial. The DISPERSE- 2 trial compared ticagrelor plus aspirin with clopidogrel plus aspirin in 990 patients with ACS with non-ST-segment elevation (NTSE).59 Patients were randomised 1:1:1, in a double-blind manner, to either of two ticagrelor doses (90 or 180mg) or clopidogrel (300mg loading dose followed by a 75mg daily maintenance dose) for up to 12 weeks.
The results of the study showed a significantly higher level of platelet inhibition with ticagrelor (90 or 180mg) versus clopidogrel (9.8, 8.0 and 8.1%, respectively). Also, a non-significant trend towards reduced rates of MI was observed in patients treated with ticagrelor (180mg) compared with those who received clopidogrel. The rate of major or minor bleeding was similar between the ticagrelor- and clopidogrel-treated groups. In patients who received clopidogrel or ticagrelor within 24 hours of CABG surgery, there was a similar rate of bleeding. However, when surgery was performed one to five days after the last dose of the antiplatelet medication, the rate of major bleeding was significantly lower in patients treated with ticagrelor than in those who received clopidogrel (36 versus 64%). These findings suggest that ticagrelor may provide improved flexibility in terms of choosing the timing and duration of dosing, as well as the timing of surgery, compared with thienopyridines such as clopidogrel.
The large, randomised, double-blind, phase III PLATO study evaluated the impact of ticagrelor versus clopidogrel on the risk of major CV events in 18,624 ACS patients (either with STEMI with scheduled primary PCI or with NSTEMI ACS).60 Patients received either ticagrelor (180mg loading dose twice daily followed by 90mg twice daily maintenance dose) or clopidogrel (300mg loading dose followed by 75mg maintenance dose). All patients also received aspirin. At 12-month follow-up, there was a significant reduction in the primary efficacy end-point (any event from the composite of death from vascular causes, MI or stroke) in patients treated with ticagrelor compared with clopidogrel (9.8 versus 11.7%; p<0.001). It was noted that the rate of definite stent thrombosis in patients who underwent PCI with stent implantation was lower in the ticagrelor- versus the clopidogrel-treated group (1.3 versus 1.9%; p=0.009). In terms of safety, there was no significant difference in the rate of major bleeding between the two groups. Non-CABG-related major bleeding was increased by ticagrelor compared with clopidogrel (4.5 versus 3.8%; p=0.03), but this finding was expected. It was also noted that the rate of major bleeding during CABG was similar with ticagrelor and clopidogrel, and this may be attributed to the reversibility of receptor binding of ticagrelor. These results suggest that ticagrelor may be more appropriate than clopidogrel for patients with ACS, particularly those who are scheduled to undergo CABG surgery, as it offers a better safety and efficacy profile than the thienopyridines.
Furthermore, it seems that ticagrelor may be suitable for long-term therapy after stent implantation as it is has been shown to be associated with a low rate of stent thrombosis. Nevertheless, the optimal duration of ticagrelor-based dual therapy needs to be further investigated. Despite the advantageous efficacy results, there have been some safety concerns raised by the results of the DISPERSE-259 and PLATO studies.60 Dyspnoea was shown to be more common with ticagrelor than with clopidogrel in both of these studies. Additionally, in the first week of treatment in the PLATO trial, ventricular pauses were more common in the ticagrelor- versus clopidogrel-treated group, although this difference disappeared after 30 days of treatment. A trend towards increased levels of creatinine and uric acid was also seen with ticagrelor compared with clopidogrel. These concerns should be taken into account when considering treatment with ticagrelor.
Dual therapy with aspirin plus clopidogrel is generally regarded by cardiologists as a gold standard treatment in patients with UA/NSTEMI ACS, those with STEMI ACS and those undergoing PCI. A current challenge with this oral antiplatelet therapy is the need to determine the optimal level of platelet inhibition to achieve a balance between the prevention of ischaemic events and minimisation of the risk of bleeding. Once determined, this information will help optimise safety and efficacy. Apart from this challenge, clopidogrel is associated with pharmacological limitations that can influence the safety and/or efficacy of the treatment. These include the delayed onset and offset of action of clopidogrel, limiting clopidogrel administration to specific times prior to surgical intervention; incorrect timing could result in either the safety or efficacy being sacrificed. There is also variability in the platelet response in different patients with ACS receiving clopidogrel, including hyporesponsiveness, which may increase the risk of adverse cardiovascular outcomes. These pharmacological limitations of clopidogrel have driven the development of new oral antiplatelet agents, including prasugrel and ticagrelor. These offer improved rates of onset and/or offset of action and more consistent and potent antiplatelet effects compared with clopidogrel.