Introduction
It is a well-known fact that cardiovascular diseases are the most common cause of mortality in highly developed countries, including the Republic of Croatia. This is also one of the main reasons why so much has been invested and achieved in both prevention and treatment of this disease group, especially for coronary heart disease (CHD). One of the major shifts was the introduction of percutaneous coronary intervention in acute myocardial infarction (primary PCI), which transformed the prognosis of survival and complications in post-infarction patients. Simultaneously with the development of new technology, there was a large step forward in our understanding of the pathophysiology of CHD, especially acute coronary syndrome (ACS). Atherothrombotic events were recognized as the basic pathological mechanism of the development and progression of both acute and chronic coronary syndromes. It has become clear that platelets have a central role in the development of coronary thrombosis based on ruptured plaque, and antiaggregation agents became fundamental for the treatment of ACS as well as ischemic complications associated with percutaneous coronary intervention (PCI). In pivotal studies, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was established as the basis of therapy in the context of ACS and PCI. Despite the proven effectiveness of DAPT, undesirable ischemic events remained relatively frequent and have encouraged the development of newer, more potent antiaggregation agents, namely prasugrel and ticagrelor. Out of these two, only ticagrelor was available in Croatia until recently, and one could argue that “the ticagrelor era” still continues today.
Pharmacodynamics and pharmacokinetics of ticagrelor
Ticagrelor is an oral antiaggregation agent that, along with clopidogrel and prasugrel, belongs to the class of P2Y12 receptor inhibitors. Unlike these two agents, which are classified as thienopyridines according to their chemical compositions, ticagrelor is a cyclopentyl triazolopyrimidine, and there are two important differences in its pharmacodynamics compared to thienopyridines due to its different chemical properties – it reversibly binds to P2Y12 receptor, while prasugrel and clopidogrel bind irreversibly, and, unlike thienopyridine, ticagrelor is not a prodrug and does not require bioactivation. It instead has a direct antiaggregation effect. Ticagrelor’s mechanism of action is different as well, because it does not preclude the binding of ADP to P2Y12 receptor. Instead, it reversibly inhibits the ADP-induced change in the receptor and activation of G-protein by binding to a site different then the ADP binding site or the binding sites of other antiaggregation agents. This is important because the receptor remains in its inactive state, and the receptor can be quickly reactivated by ADP after releasing ticagrelor. From a clinical aspect, these two properties explain the quick and safe onset of action (independent of bioactivation), as well as the relatively quick recovery of platelet aggregation and reduction in bleeding risk. Ticagrelor is quickly metabolized in the liver by the CYP3A4/5 enzyme, and the main metabolite of ticagrelor breakdown is almost equally effective in inhibiting the P2Y12 receptor. Due to the pharmacokinetic properties described above, ticagrelor has a much faster onset of action, a significantly higher level of platelet inhibition, and a quicker cessation of pharmacodynamic activity compared with clopidogrel.
We now know that there are effects of ticagrelor that are independent of P2Y12 receptor inhibition. Most of these effects are a consequence of increased concentration of adenosine, which has an additional effect on microcirculation and is presumed to reduce myocardial reperfusion injury. Adenosine is also thought to be one of the main mechanisms behind the adverse effects of ticagrelor – dyspnea and, less commonly, bradycardia.
Indication range and duration of ticagrelor therapy
Indications for the use and choice of antiaggregation therapy, including ticagrelor, depend on several different factors that can collectively be described as a relationship between ischemic risk and the risk of bleeding. Ischemic risk depends primarily on the diagnosis itself and is known to be significantly higher in ACS than in chronic coronary syndrome (CCS). Furthermore, it matters whether a patient has undergone interventional treatment and had a stent implanted or has only had medication treatment. Until recently, the type of stent implanted also made a difference, but today we practically only use drug-eluting stents (DES). Indications are also influenced by the chosen combination of antiaggregation agents, in particular on whether the medications are administered as monotherapy or dual antiaggregation therapy, or even triple therapy in patients receiving anticoagulant treatment. Different duration of antiaggregation therapy is also relevant, since we normally try to make it as short as possible in patients with high bleeding risk, therapy is long-term or even life-long whereas in patients with high ischemic risk and low bleeding risk. In light of the above, ticagrelor’s indication range should be primarily viewed through patients with ACS and those with one of the CCS.
Acute coronary syndrome
Current guidelines for the treatment of patients with ST-elevation and non-ST-elevation ACS recommend DAPT with aspirin and ticagrelor or prasugrel for twelve months (1) (Table 1). Ticagrelor should be given with aspirin at a loading dose of 180 mg and then continued at a dosage of 2x90 mg. Compared with prasugrel, ticagrelor has several advantages – it is indicated regardless of the treatment strategy, including both patients undergoing interventional treatment (PCI) and patients receiving only medication treatment. Furthermore, the standard dose of ticagrelor can be used relatively safely in patients who are already receiving therapy with clopidogrel, as well as in those with low body weight (<60 kg) and advanced age (>75 years). Ticagrelor became a part of daily clinical practice of treating ACS in 2009, when the results of PLATO, a pivotal study with ticagrelor, were published. (2) PLATO was a randomized, multicentric, double-blind study on the efficacy of ticagrelor (180 mg loading dose, 2x90 mg maintenance dose) versus clopidogrel as the current gold standard (300-600 mg loading dose/75 mg maintenance dose). Ticagrelor therapy was demonstrated to be significantly more effective in reducing the combined outcome of death and ischemic events after 30 days (4.8 vs. 5.4%; P = 0.045), and ticagrelor superiority was maintained even after 12 months, with a relative risk reduction of 16% (9.8 vs. 11.7%, P <0.001). It should be noted that slightly higher rates of major bleeding were observed with ticagrelor in the PLATO study, but there was no difference in critical bleeding between these two agents. From a clinical point of view, it is very interesting that there was no difference in major bleeding between patients who underwent coronary artery bypass grafting, noting that ticagrelor was discontinued 24-72 hours before the surgery, while clopidogrel was omitted 5 days before the procedure. This directly demonstrated the pharmacokinetic advantage of ticagrelor, specifically, its quicker cessation of effect. One of the most important results of the PLATO study was a significant reduction in mortality associated with ticagrelor therapy. It should again be emphasized that ticagrelor’s anti-ischemic efficacy vs. clopidogrel was independent of the chosen treatment strategy, whether the treatment was interventional or conservative. Based on this result, all guidelines listed ticagrelor as the antiaggregation agent of choice for DAPT in patients with ACS only receiving medication treatment (Table 1).
It is worth noting that ticagrelor was associated with more frequent adverse effects in the PLATO study, the most common of which was dyspnea – occurring in up to 15% of patients during the first week of treatment, in most cases in mild form and not requiring treatment discontinuation. Today, after more than ten years of clinical experience with ticagrelor, we can say that dyspnea most commonly occurs during the first 48 hours post-administration and subsides within a few days. Dyspnea as a symptom must not be underestimated because it could also be equivalent to angina, i.e., a potential in-stent thrombosis, which is why a follow-up ECG should be performed in these patients.
Chronic coronary syndrome
As mentioned in the introduction, CCS carries a significantly lower ischemic or thrombotic risk compared with ACS, so potent antiplatelet agents are used less frequently. The indication range of ticagrelor in patients with CCS can be divided into three zones (Table 1) – (1) long-term (>12 months) use of ticagrelor in DAPT in high ischemic risk, (2) use of ticagrelor as part of DAPT within 12 months of PCI, and (3) ticagrelor monotherapy.
(1) Long-term use of ticagrelor in DAPT – The results of several studies have demonstrated a positive effect of combining ticagrelor and aspirin in long-term therapy, i.e., 12 months after ACS or after PCI. The first and fundamental study was PEGASUS TIMI 54, which randomized patients with a previous infarction (most of them had undergone PCI) to aspirin with either ticagrelor 2x60 or ticagrelor 2x90 vs. aspirin and placebo. (3) After an average follow-up period of 33 months, the ticagrelor group had a significantly lower rate of cardiovascular and cerebral events, but at the expense of increased incidence of bleeding. The group receiving the lower 2x60 mg dosage of ticagrelor had significantly lower rates of bleeding vs. the group receiving the higher dosage. It should be noted that there were no differences among the three groups in the incidence of intracranial and critical bleeding. This study is extremely important as it demonstrated the efficacy of long-term DAPT in patients with high ischemic risk. Similar results were observed in THEMIS-PCI, a study that demonstrated that long-term therapy with ticagrelor and aspirin can effectively reduce ischemic events in patients with diabetes and post-PCI status. Guidelines of the European Society of Cardiology (ESC) recommend that DAPT with ticagrelor 2x60 mg can be prolonged for more than 12 months in post-myocardial infarction patients or those with high ischemic risk (4), based on the results of PEGASUS (3) and THEMIS-PCI (5).
(2) Use of ticagrelor as part of DAPT within 12 months of PCI – Although no large-scale randomized studies have been performed, ESC guidelines clearly state that the use of ticagrelor can be considered in specific high-risk situations involving elective PCI, such as suboptimal stent position or other characteristics of the procedure associated with a high risk of in-stent thrombosis, complex “left main”, or stenting in multivessel disease. (4)
(3) Ticagrelor monotherapy – If clopidogrel is administered alone in post-PCI patients with aspirin intolerance, there is an increased risk of in-stent thrombosis. This is why ESC guidelines provide the option of ticagrelor as monotherapy in order to achieve a more potent antiaggregation effect. (4) The TWILIGHT study, published in 2019, provided the option of another antiaggregation therapy – in post-PCI patients with high ischemic risk and high bleeding risk, after three months of DAPT with ticagrelor, continued ticagrelor monotherapy lasting up to 12 months demonstrated a significant reduction in bleeding by 44%, without any increase in the risk of ischemic events. (6)
Conclusion
In the past decade, ticagrelor has become the basis of dual antiaggregation therapy in patients with ST-elevation and non-ST-elevation acute coronary syndrome, regardless of the treatment strategy. It can also be used in patients with complex PCI during the first 12 months, and used in patients with high ischemic risk even longer than 12 months, or used long-term at a reduced dose.