Among the many new antiplatelet substances that are currently being developed, different new P2Y12 antagonists are most likely to soon be introduced into clinical routine. The third orally available Thienopyridine drug, prasugrel, and the two non-thienopyridine antagonists of P2Y12 cangrelor (intravenous administration) and AZD6140 (orally applicable), are currently being tested in phase III studies or are already being launched by the manufacturers, after having shown promising results in phase II studies in terms of efficiency and safety ().
Figure 3 Potential new targets of antiplatelet substances. Aside from the development of further P2Y12 ADP receptor antagonists, which are either thienopyridines or non-thienopyridine structured and may have improved efficacy and advantageous pharmacokinetics, (more ...)
Similarly to clopidogrel, prasugrel is a prodrug, which only after hepatic metabolism releases its clinically active compound. In preclinical evaluation, it is 10 times more potent than other thienopyridines. Its safety and a comparable efficiency of prasugrel in comparison with clopidogrel (300 mg loading dose, 75 mg maintenance dose) was shown in the (JUMBO)-TIMI 26 study (Wiviott et al 2005
). In the recently published TRITON-TIMI 38 study, prasugrel treatment was associated with a significantly reduced rate of the primary end point, which was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with acute coronary syndromes, when compared with clopidogrel 300 mg loading and 75 mg maintenance dose. However, this advantage did not result in a difference in overall mortality, and, more importantly there was an increase in rates of major bleeding, including fatal bleeding (Wiviott et al 2007
). As the currently running phase III study (PRINCIPLE)-TIMI 44 also incorporates more up to date, increased doses of clopidogrel it will not only deliver important information about prasugrel, but will also provide valuable information about the clinical consequences of an increased dose of clopidogrel, which so far is not sufficiently backed by data from large patient cohorts.
Cangrelor or AZD6140, on the other hand, are directly acting reversible inhibitors at the P2Y12
receptor. Potential advantages of cangrelor and AZD6140 in comparison to clopidogrel likely lie in their different pharmacokinetics, which include more rapid onset and loss of action (Greenbaum et al 2006
). Due to this, cangrelor is also being investigated as an alternative to GPIIb/IIIa receptor antagonists in the CHAMPION-PCI and CHAMPION-PLATFORM studies, whereas AZD6140 is being tested against clopidogrel in the setting of STEMI and NSTEMI in the PLATO study. These drugs, due to the quicker loss of action, bear the potential to have improved safety profile in specific clinical situations such as in the setup of perioperative coronary angioplasty.
Besides the newly developed P2Y12
receptor antagonists, there are antiplatelet strategies currently under development, which target structures of platelets that so far have not been subject to pharmacological treatment and thus truly incorporate innovative mechanisms of action. Examples are antibodies or aptamers that target the collagen receptor GPVI or the vWF receptor GPIb (). Both of these targets have gained attention rather late in comparison to the above mentioned platelet receptors as therapeutic targets, yet due to the important role of these structures in platelet pathophysiology may pose interesting alternatives for treatment and even extent the scope of indications of antiplatelet drug. Moreover, in animal experiments, these antibodies not only have antiplatelet, but also antiatherosclerotic properties and also may be associated with lower bleeding risks (Kleinschnitz et al 2007
Thromboxane receptors represent interesting targets for newly developed antiplatelet agents. Interestingly, in animal models, drugs like S18886, a selective thromboxane receptor antagonist, exert properties beyond inhibition of platelet aggregation, by also improving endothelial function (Belhassen et al 2003
), or inhibiting atherosclerosis development (Worth et al 2005
). Although no clinical studies for S18886 are at hand yet, it seems to have excellent antithrombotic activity in an animal model of stent thrombosis (Vilahur et al 2007
). Another substance that targets the thromboxane receptor also inhibits thromboxane synthase, and thus exerts dual inhibitory action. This drug, picotanide, has proved to be more effective than aspirin in the DAVID study that addresses its use in the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease (Neri Serneri et al 2004
Other interesting targets are the protease-activated receptors (PAR), which are physiological targets of thrombin that are not only expressed on platelets, but also on endothelial and vascular smooth muscle cells and on macrophages (). As experimental findings have shown that PAR-dependent thrombin actions not only include platelet activation, but also the development of intimal hyperplasia, regulation of vessel tone, inflammation and endothelial barrier function, the various drugs that are currently being developed to target these structures, could potentially not only afford antithrombotic, but different, more profound antiatherosclerotic actions in patients (Leger et al 2006