The usual underlying mechanism of acute coronary syndromes (ACSs) is a thrombotic event caused by the rupture or erosion of an atherosclerotic plaque. In this scenario, platelets and thrombin are key players. Thus, understanding the physiopathology of platelet activation is of paramount importance in the treatment of acute coronary ischaemia. There is ample evidence showing that adequate antiplatelet therapy improves survival and reduces new coronary events.
Platelet activation occurs through the complex process of transmembrane signalling after the exposure to platelet agonists. There are several categories of antiplatelet agents, acting through various pathways, that inhibit platelet activation (see Figure 1). Aspirin interferes with the arachidonate-thromboxane A2 pathway by irreversibly inhibiting cyclo-oxigenase-1. Thienopyridines modulate the adenosine diphosphate (ADP) pathway, by irreversibly blocking the ADP receptor P2Y12. New drugs such as ticagrelor, cangrelor and elinogrel also inhibit ADP-induced aggregation, although their binding to the P2Y12 receptor is reversible. Thrombin is a key regulator of platelet activation through the protease-activated receptor-1 (PAR-1) and the link between coagulation activation and platelet aggregation. Vorapaxar (SCH 530348) is a potent antagonist of the platelet thrombin receptor PAR-1 and the first to have been studied in coronary diseases. Finally, glycoprotein IIb/IIIa inhibitors block the final common pathway in the process leading to platelet aggregation. The use of any one or a combination of several of them achieves an important inhibition of platelet function in patients with acute coronary syndromes. This article briefly reviews the usual treatment and describes the new antiplatelet agents in the treatment of acute coronary ischaemia.
Classic Antiplatelet Drugs
Aspirin, which blocks the thromboxane-mediated pathway, reduces by approximately 40 % the risk of death from cardiovascular causes, new myocardial infarction and recurrent ischaemia, as shown in several trials. Efficacy has been demonstrated within a wide range of doses although 75 to 350 mg are the most used; higher doses are not more effective and are less well tolerated.1
Clopidogrel, a thienopyridine derivative, is an antiplatelet agent that inhibits ADP platelet-induced aggregation. When administered with aspirin, it has been shown to be effective in reducing death, myocardial infarction (MI), stroke and stent thrombosis. In the Clopidogrel in unstable angina to prevent recurrent events (CURE)2 a randomised, double-blind, placebo-controlled trial, 12,652 patients with ACS without ST-segment elevation were randomised to receive clopidogrel (300 mg loading dose and 75 mg daily) or placebo in addition to aspirin. The primary outcome, a composite of death from cardiovascular causes, nonfatal MI or stroke, occurred in 9.3 % of the patients in the clopidogrel group and 11.4 % in the placebo group. The recurrent angina and in-hospital refractory ischaemia were also higher in the placebo group. This antithrombotic efficacy was accompanied by an increase in the rate of bleeding; major bleeding was significantly more common in the clopidogrel group and in patients undergoing surgery who took clopidogrel five days before surgery.
However, some shortcomings of clopidogrel have been described after the CURE trial and merit some discussion. Clopidogrel is a prodrug converted in vivo to an active metabolite. Its bioavailability is influenced by ABCB1 polymorphism at the time of its absorption and by metabolism through the cytochrome P-450 pathway. Clopidogrel is activated in a two-step process in the liver, influenced by CYP2C19 and CYP3A polymorphisms. The activity of hepatic cytochrome isoenzymes are influenced by drug-to-drug interactions, single nucleotide polymorphisms and environmental influences such as smoking; other associated comorbidities (diabetes, body weight, etc) may also influence the thrombotic burden. This substantial variability in pharmacodynamic and pharmacokinetic properties has a practical impact. In some patients, its antiplatelet effects are delayed or not effective, with an important inter-individual variability in platelet inhibition due mostly to differences in the metabolism of the prodrug. All of this results in reduced platelet inhibition despite clopidogrel in about 30 % of patients. These patients are labelled as clopidogrel nonresponders. Clopidogrel nonresponders present a poor outcome after percutaneous coronary intervention (PCI) and a higher rate of stent thrombosis.3 Finally, the long-term platelet inhibition due to the irreversible inhibition of P2Y12 is a problem when patients need urgent coronary artery bypass grafting (CABG) or other surgical procedures within five days of stopping clopidogrel treatment.
Other approaches have been tested to mitigate some of these limitations. A loading dose of 300 to 600 mg of clopidogrel is mandatory to reduce the delayed onset of the antiplatelet effect to three to five hours. The recent double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin study Clopidogrel optimal loading dose usage to reduce recurrent events (CURRENT-OASIS 7) tested a 600 mg loading dose and 150 mg daily for seven days in individuals undergoing PCI for ACS4 and showed a reduction in cardiovascular events and stent thrombosis.
Patient-tailored treatment has been proposed to solve the problem of clopidogrel nonresponders. Bonello et al.5 recently showed that adjusted clopidogrel loading dose can optimise platelet reactivity in patients with non-ST-segment elevation ACS undergoing PCI. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein index, using a cut-off value of ≥50 % to define high on-treatment platelet reactivity. Although the patient-adjusted loading dose of clopidogrel improved platelet reactivity inhibition in most patients, it failed in about 10 % of cases despite 2,400 mg of clopidogrel. Moreover, tailored treatment with clopidogrel has not been implemented in routine clinical practice because there is no consensus recommendation.
Antiplatelet agents increase the risk of gastrointestinal bleeding and other medications (such as anticoagulants, steroids or nonsteroidal anti-inflammatory drugs), Helicobacter pylori infection and prior gastrointestinal bleeding increase risk of bleeding. Therefore, a proton pump inhibitor (PPI) is recommended in patients with risk factors for gastrointestinal bleeding.6 Since PPIs are metabolised by the hepatic cytochrome P-450, they may interfere with clopidogrel activation. Platelet function tests showed less platelet inhibition with clopidogrel in patients treated with PPI. However, there is no definitive evidence associating PPI with a worse clinical outcome. A subanalysis of the results of the Assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel thrombolysis in myocardial infarction (TRITON-TIMI 38) trial7 did not show an increase in major adverse clinical events with the use of PPI concomitantly with thienopyridines.
Although the limitations of clopidogrel can be reduced in part by increasing the dose, the lack of efficacy in some patients and the delayed offset in all cases are a problem. In recent years, new and more potent antiplatelet drugs have been tested in the treatment of ACS (see Table 1).
New P2Y12 Antagonists
Prasugrel
Prasugrel is a new thienopyridine that inhibits ADP-induced platelet aggregation. Like clopidogrel, it requires conversion to an active metabolite before binding to the platelet P2Y12 receptor. Ex vivo and in vitro studies demonstrated that the active metabolites of both drugs have the same potency, however, the presence of CYP2C19 alleles with less function does not seem to have a clinical impact in prasugrel-treated patients.8 In addition, the antiplatelet activity is achieved much faster than with clopidogrel. The degree of inhibition of platelet aggregation obtained with prasugrel within 30 minutes after treatment is similar to the peak effect of clopidogrel six hours after administration.9
Prasugrel was tested in TRITON-TIMI 38.10 The study included 13,608 patients at moderate-to-high risk for unstable angina or MI, with or without ST-elevation, who required PCI. They were randomised to receive a 60 mg loading dose of prasugrel followed by 10 mg/day, or 300 mg loading dose of clopidogrel followed by 75 mg/day. The primary efficacy end point (death from vascular causes, nonfatal MI or nonfatal stroke) occurred in 12.1 % of the patients receiving clopidogrel and 9.9 % of patients receiving prasugrel. In this study, the risk of stent thrombosis was also lower; the rate of drug-eluting stent thrombosis was 0.84 versus 2.31 % and of bare metal stents 1.27 versus 2.41 %, for prasugrel- and clopidogrel-treated patients, respectively.11
However, this benefit was accompanied by a higher incidence of major and fatal bleeding complications. The three subgroups with clinical harm or less net clinical benefit were patients ≥75 years of age, patients weighing <60 kg and patients with previous stroke.
Some of the limitations of clopidogrel are overcome with prasugrel, making it now the best option in high thrombotic risk cases undergoing PCI, such as patients with diabetes, previous stent thrombosis or those with AMI undergoing primary angioplasty. However, its irreversibility and the increased haemorrhagic risk remain a problem.
Ticagrelor
Ticagrelor is an oral, reversible, direct-acting inhibitor of the ADP receptor P2Y12. Platelet inhibition is more rapidly and uniformly effective with ticagrelor, and results in less variability than with clopidogrel. In contrast to clopidogrel, the antiplatelet effect of ticagrelor is independent of CYP2C19 genotype.12
Ticagrelor has been evaluated in the Study of platelet inhibition and patient outcomes (PLATO)13 that randomised 18,624 patients with moderate-to-high risk ACS to ticagrelor (180 mg loading dose, 90 mg twice-daily thereafter) or clopidogrel (300 to 600 mg loading dose, 75 mg daily thereafter). Importantly, patients entered the study regardless of the treatment strategy (invasive or conservative). The primary endpoint, a composite of death from vascular causes, MI or stroke, occurred in 9.8 % of patients receiving ticagrelor and in 11.7 % of the patients treated with clopidogrel. The rates of death from any cause and of stent thrombosis were also reduced with ticagrelor. No significant difference in the rate of PLATO-defined major bleeding was found in either group, although there was a higher incidence of TIMI major non-CABG-related bleeding in patients who received ticagrelor. Other side effects were dyspnea and ventricular pauses. However, discontinuation of treatment because of dyspnea occurred in 0.9 % of patients in the ticagrelor group and no significant increase was observed for pacemaker implantation. This promising drug is now being evaluated by the health authorities and is expected to be available for clinical use shortly. The advantage of ticagrelor over prasugrel is that it has been tested in the whole spectrum of ACS, independently of an invasive strategy and there are no ‘nonresponders’.
Cangrelor
Cangrelor is a potent inhibitor of ADP-induced aggregation, with a high affinity for the P2Y12 receptor. It is administered intravenously, has a plasma half-life of three to six minutes and is immediately active after infusion: platelet function normalises within 30 to 60 minutes after discontinuation. The mean inhibition of platelet aggregation with cangrelor is similar to that achieved with abciximab, with less prolongation of the bleeding time. These characteristics make cangrelor an excellent drug for patients who require a rapid and profound but reversible platelet inhibition.
Two phase III randomised clinical trials tested cangrelor compared with placebo in patients undergoing PCI. In the CHAMPION PCI trial,14 patients were randomised to infusion of cangrelor or treatment with clopidogrel before PCI. In the CHAMPION PLATFORM trial,15 cangrelor was administered after PCI. Both trials were prematurely stopped for apparent futility because no differences were achieved in the primary end point, a composite of death for any cause, MI or ischaemia-driven revascularisation at 48 hours, although in the CHAMPION PLATFORM trial the rate of stent thrombosis was reduced with cangrelor. The definition of MI and the timing of cangrelor administration may have played a role in those results.
Elinogrel
Elinogrel is a direct-acting, reversible P2Y12 inhibitor that can be administered both intravenously and orally. Two pharmacologic properties make it an interesting antiplatelet agent. It is the only P2Y12 receptor inhibitor available in oral and intravenous formulation and both formulations are pharmacologically identical. Studies in healthy volunteers showed great platelet inhibition without clinically relevant adverse effects. A randomised phase IIA trial, Safety and efficacy study of adjunctive antiplatelet therapy prior to primary PCI in patients with STEMI (ERASE-MI),16 assessed the safety and tolerability of elinogrel administered as a single intravenous bolus before PCI in 70 patients with ST-elevation MI. Although a small study, bleeding events were infrequent and appeared to be similar between elinogrel and placebo. A randomised, double-blind, phase IIB trial, Novel intravenous and oral P2Y12 inhibitor, in non-urgent PCI (INNOVATE-PCI),17 compared intravenous followed by oral elinogrel with clopidogrel in patients undergoing non-urgent PCI. Safety results were presented at the 2010 European Society of Cardiology meeting, but have not yet been published. There were no TIMI major bleeding events and no significant differences between clopidogrel and either the 80 mg or the 120 mg IV elinogrel doses with respect to TIMI major or minor bleeding at 24 hours, nor with the maintenance oral doses of 100 mg or 150 mg during 120 days.
Thrombin Receptor Antagonist
Vorapaxar
Vorapaxar (SCH 530348) is a potent antagonist of the platelet thrombin receptor PAR-1, blocking thrombin-mediated platelet activation without interfering with thrombin-mediated cleavage of fibrinogen. It has a rapid onset, with great inhibition of platelet aggregation within one to two hours, according to the loading dose. Bleeding time or coagulation time did not increase in preclinical and early clinical studies. In the TRA-PCI study,18 a phase II trial, 573 patients with ACS who underwent PCI were randomised to vorapaxar (loading dose 10, 20 or 40 mg) or placebo in addition to aspirin and clopidogrel. At 60 days, maintenance doses of 0.5, 1 or 2.5 mg per day were continued. It was not associated with an increase in TIMI major plus minor bleeding versus placebo. However, the phase III TRACER study that randomised patients within seven days of an ACS has been prematurely stopped because of bleeding problems. The other phase III trial, TRA 2P-TIMI 50 in secondary prevention, is still ongoing but vorapaxar has been discontinued in patients with previous stroke or in those who have had a stroke during the study period. The complete details of the bleeding problems are not yet available (February 2011).
Inhibitors of Phosphodiesterase Type III
Cilostazol
Cilostazol is a selective inhibitor of phosphodiesterase type III that inhibits platelet aggregation in platelets and in the vascular wall and increases ADP inhibition. In the Efficacy of cilostazol on ischemic complications after drug-eluting stent implantation trial (CILON-T),19 960 patients with coronary artery disease undergoing PCI with drug-eluting stent were randomised to receive a 200 mg loading dose of cilostazol followed by 100 mg twice-daily for six months.
All patients were given aspirin and clopidogrel before coronary intervention. The results showed that triple antiplatelet treatment was associated with an increased platelet reactivity inhibition, but this effect did not translate into any clinical benefit. Bleeding complications did not differ between groups.
In this study, an important number of patients had high post-treatment platelet reactivity despite the addition of cilostazol to clopidogrel. At the moment, the role of cilostazol in patients presenting ACS has not been tested and according to the above results, it does not seem to have any triple therapy role in patients undergoing PCI.
Final Considerations
The anti-aggregation armamentarium is rapidly growing and most new drugs have been tested in ACS. Because the new treatments are added to aspirin and even to aspirin and clopidogrel, bleeding has increased, but at the same time, greater efficacy has been demonstrated in several trials, as discussed above. Thus, it is mandatory that clinicians individualise antithrombotic treatment, including not only anti-aggregation agents but also anticoagulants. The reduction in the rate of ischaemic events with antiplatelet drugs, including both oral agents (aspirin and clopidogrel) and intravenous ones (glycoprotein IIb/IIIa receptor antagonists), has uniformly been accompanied by an increase in bleeding: more consistent platelet inhibition is linked to an increase in bleeding.
Therefore, it is essential that clinicians identify subgroups of patients in whom bleeding is likely to occur. Several studies, especially the TRITON TIMI 38, identified an excess of bleeding, and therefore less clinical benefit, in patients with history of stroke or transient ischaemic attack, the elderly (age ≥75 years) and those with a body weight <60 kg. For the last two groups of patients, both the United States Food and Drug Administration and European Medicines Agency have suggested that the maintenance dose of prasugrel be reduced to 5 mg daily. The effectiveness of a lower maintenance dose in the elderly is currently under investigation (NCT00699998). Similarly, the benefit of ticagrelor appeared to be attenuated in patients weighing less than the median weight for their sex.
Intensive antiplatelet therapy is a problem in terms of increased bleeding in patients who need to undergo CABG and who are taking long-life drugs such as clopidogrel and prasugrel. New antiplatelet drugs with a shorter half-life, like ticagrelor, or elinogrel in the future are a necessary addition to the actual armamentarium in the treatment of ACS, shortening the time to surgery for patients taking aspirin and an ADP receptor blocker.
Finally, we need to reconsider how to plan future trials of potent antithrombotic drugs. It seems that triple anti-aggregation for secondary prevention can be harmful, as indicated by the early stop to the TRACER study. This needs to be taken into account also for the oral anti-Xa factors that are currently undergoing extensive testing in phase II and III trials.
In conclusion, the correct choice of antiplatelet therapy should be based on the patient’s thrombotic and bleeding risks. New therapeutic approaches to ACS treatment provide a wide range of possibilities, but a new perspective on how to use and combine new drugs is urgently needed to take advantages of the efficacy and avoid bleeding.