Ticlopidine is the first thienopyridine drug that started to be used in the clinical practice. It first proved to be efficient in the long-term therapy after ischemic stroke even in case of claudication and a 46% reduction was achieved in cardiovascular mortality and myocardial infarction (MI) in the first six months in the placebo-controlled study for the treatment of unstable angina pectoris (AP) (1). The combination of ASA and ticlopidine has facilitated the use of coronary stents, and in one comparative study with clopidogrel after elective stenting, it showed a better effect in the first month after PCI (2). It is also the only P2Y12 inhibitor that has an approved indication for application after the elective stent.

However, its delayed onset of action (24 to 48 hours after administration) makes it unsuitable in ACS, as well as hematological side-effects (especially thrombotic thrombocytopenic purpura and aplastic anemia), which usually occur in the first three months of application and requirements for frequent blood count control have limited the administration of this drug, and it has been squeezed out from the wider use at the time of introducing clopidogrel in the therapy. Since genetic variability has not been proved in the metabolism of ticlopidine and it is effective in 96.5% of patients with proved resistance to clopidogrel, it remains to be an alternative for patients who do not tolerate clopidogrel and in whom it is inefficent (3, 4).

After ticlopidine, the following thienopyridine clopidogrel was introduced in the therapy which had a major advantage over its predecessor which was much faster pharmacodynamic effect (two hours after the “loading” dose of 300-600 mg) which made it superior when performing PCI in ACS, and it also had less hematological side effects than ticlopidine and better gastrointestinal tolerance.

Clopidogrel monotherapy proved to be somewhat more effective ASA in secondary prevention of ischemic events in patients with peripheral vascular disease, ischemic stroke and MI in the CAPRIE study (5). However, it has not replaced ASA due to the high cost compared to it, and it is used as an alternative to ASA in the monotherapy in case of its intolerance. Numerous tests in ACS and after PCI have shown the superiority of the combination of clopidogrel and ASA compared to ASA alone during one-year application, so that it has become a standard therapy in patients with ACS and after stent implantation (6-10).

The main disadvantages of clopidogrel are still relatively slow onset of action, high inter-individual differences in the effect of the irreversible effect on platelet aggregation. Clopidogrel activation process is responsible for the first two ones that is carried out in two phases, and includes a large number of cytochrome P450 enzymes that are susceptible to drug interactions and genetic polymorphisms. Patients with the genetic polymorphism have no or limited metabolism of clopidogrel and thus resistance to its effect (11).

The attempts to predict the effect of clopidogrel by measuring platelet aggregation have not proved effective so far (e.g. the recent ARCTIC trial (12) in which the adjusted antiplatelet therapy was compared to standard therapy after PCI), so there is no sense to determine platelet aggregation for determining the efficacy of clopidogrel, and other antiplatelet drugs at this moment (13).

The question as to the interaction of clopidogrel with proton pump inhibitors (which has been much discussed in recent years), has more theoretical than practical significance (14, 15).

Being most recent one in the thienopyridine class, it is more effective than ticlopidine and clopidogrel, primarily due to a faster and more efficient metabolism (only in one phase), so that the platelets are affected by several active metabolites. It has a faster onset of action and a stronger antiaggregation effect than clopidogrel. Compared to it, it shows less variability in effect, and there is no evidence that genetic polymorphism in the CYP isoenzymes affects its metabolism. In TRITON TIMI 38 trial in patients with ACS it has proven to be superior to clopidogrel in reducing ischemic events (particularly in patients with STEMI or diabetes), but at the expense of a slightly higher risk of bleeding, especially fatal one (21 prasugrel versus 4 clopidogrel). The effect was visible in all 15 months as long as an average follow-up of patients lasted in the study. The in-stent thrombosis was reduced by 50%, both in BMS and DES. The risk of bleeding was increased in patients over 75 years of age, with less weight and previous stroke, so administration of the medicine was not recommended in these patients (stroke contraindication), or if the administration is necessary, they should be given a reduced dose of 5 mg. The risk of bleeding was higher by four times in patients who underwent the coronary artery bypass grafting than in the group receiving clopidogrel and it was also increased in other operations in the first week after they stopped taking the medicine (16).

The study TRILOGY compared prasugrel vs. clopidogrel in patients with ACS, but who were treated pharmacologically. There was no statistically significant difference between the two drugs, but in patients with angiographically documented coronary artery disease, prasugrel was superior to clopidogrel in reducing ischemic events (12.8% vs. 16.5%, p = 0.001) (17).

Ticagrelor is the first representative of a new group of P2Y12 receptor inhibitors, the so-called cyclopen-tyltriazolo-pyrimidines. It was created in the process of searching orally active mimetic ATP, the natural P2Y12 receptor antagonist. Ticagrelor reversibly binds with the receptor with a more potent and more rapid antiplatelet effect of clopidogrel. In the PLATO study it showed, compared to clopidogrel, a relative reduction by 16% of risk-primary endpoint (the composite of cardiovascular mortality, myocardial infarction and stroke) with an insignificant increase in the risk of major bleeding (18). A statistically significant reduction of ischemic events (including stent thrombosis) was proved in the substudy PLATOINVASIVE, but with no increase in major bleeding as compared to clopidogrel (19).

It was also safer in patients who underwent coronary artery bypass grafting, although bleeding was more extensive in patients who did not undergo the surgery. While clopidogrel and prasugrel showed no reduction in mortality, ticagrelor had a 22% lower mortality despite the potent antiplatelet effect (20).

The relatively short half-life of the drug and taking the drug twice a day requires good patient compliance which should be permanently insisted on. You should be cautious in patients with a high risk of bleeding and comorbidity.

Although the drug was registered in the European Union and the United States of America in 2011, and is included in the guidelines of the European Society of Cardiology (ESC) for the treatment of ACS, as well as in the British NICE guidelines, a series of articles published in 2013 has raised doubts about the results and methodology of the PLATO study, so that in September 2013 the U.S. Department of Justice began an investigation on the implementation of the study (which results are still awaited). It is interesting to note that the regulatory status of the drug has remained unchanged in spite of that investigation (21, 22).

There are several antiplatelet drugs included in the clinical trials whose action is enabled by various mechanisms, whereas voraxapar is one of them being closest to the clinical use and inhibiting activation of platelets via thrombin PAR-1 receptors. At this point, its registration in the indication of secondary prevention of myocardial infarction is underway, while the negative safety profile (negative ratio of prevention of ischemic events vs. bleeding) excluded this drug in the treatment of ACS (23).

ESC Guidelines for the treatment of ACS, especially in patients undergoing PCI, prefer ticagrelor and prasugrel to clopidogrel, where ticagrelor is the drug of choice. Clopidogrel is mentioned as a treatment option, if the first two drugs are unavailable or contraindicated. Dual therapy should be conducted 12 months after PCI (24, 25).

American guidelines for PCI in ACS place the below specified drugs in the same level of the recommendation: clopidogrel, prasugrel and ticagrelor thereby recommending that they should be administered in the dual therapy with ASA in the further 12 months’ period.

In case when PCI is not associated with ACS, the only P2Y12 receptor antagonist that is recommended is clopidogrel with a recommendation, that after BMS it should be administered in dual therapy for at least one month (one year optimally), and after DES it should be administered mandatory for one year with the possibility of further extension of this term (26).

The English NICE guidelines for secondary prevention of myocardial infarction recommend clopidogrel for dual antiplatelet therapy in those patients with indicated permanent anticoagulation therapy. The length of administering dual antiplatelet therapy after ACS and PCI, that is, elective PCI, is consistent with mentioned guidelines. They explicitly state that ticagrelol and prasugrel are not to be administered together with warfarin, and also do not recommend the administration of new oral anticoagulants (dabigatran, rivaroxoban and apixaban) with dual antiplatelet therapy (27, 28).

All four P2Y12 receptor inhibitors discussed in this article are registered in Croatia, and all four of them are listed in the List of the Croatian Health Insurance Fund. Out of these new drugs, there are two new ones (Efient® — prasugrel and Brilique® — ticagrelor) with a relatively high surcharge ranging from HRK 214 to HRK 324 per box of the drug. This is the reason why their use is greatly limited in accordance with Croatian guidelines for the treatment of ACS.

Although the literature mentions some opinions according to which their advantage over clopidogrel is not so great to justify the difference in price (29), their listing in the List of Essential Medicines of the Croatian Health Insurance Fund (without a surcharge) would allow a better treatment for our coronary patients, especially in ACS, but the question is how viable it is in this hard economic situation.