Ticagrelor: the silence of the platelets

Keywords::

• acute coronary syndrome
• major adverse cardiac events
• percutaneous coronary syndrome
• ticagrelor

Antiplatelet therapy is the cornerstone of the care of acute coronary syndrome (ACS) patients. Since the early days of percutaneous coronary intervention (PCI), it was observed that potent platelet inhibition is mandatory to prevent major adverse cardiac events (MACE) such as cardiovascular deaths, myocardial infarction (MI) and stent thrombosis. Consistently, ticlodipine then clopidogrel were used to prevent thrombotic events in ACS and PCI patients. However, these drugs have several limitations whether in their safety (ticlodipine) or in their efficacy in ACS patients which prompted the development of more potent oral antiplatelet agents including prasugrel and ticagrelor.

Ticagrelor is part of a new class of agent inhibiting the platelet P2Y12 receptor. It is the first P2Y12 ADP receptor that reduced cardiovascular mortality in ACS patients undergoing either invasive (e.g., PCI, coronary artery bypass grafting (CABG)) or non-invasive management [1,2]. This benefit is explained by lower rates of MI, stent thrombosis and a trend toward a reduction of non-cardiovascular deaths. Unlike clopidogrel or prasugrel, ticagrelor is an oral antiplatelet agent that reversibly inhibits platelets P2Y12 receptors to adenosine diphosphate. Further, unlike thienopyridines ticagrelor does not require hepatic biotransformation to become active.

The higher efficacy of ticagrelor in part relies on a more intense and consistent platelet reactivity inhibition compared with clopidogrel that is independent from genetic polymorphisms [3,4]. Furthermore, some authors suggested that pleiotropic effects potentially mediated by adenosine could be responsible for the reduction in cardiovascular mortality observed in the PLATO trial (Table 1) in the ticagrelor arm compared with clopidogrel. Trials are underway to investigate this hypothesis.

Table 1. Hazard ratio of the PLATO and TRITON trials.

	Hazard ratio for ticagrelor group (95% CI)*	Hazard ratio for prasugrel group (95% CI)*
Death from vascular causes, MI, stroke	0.84 (0.77 – 0.92), p < 0.001	0.81 (0.73 – 0.90), p < 0.001
Death from cardiovascular causes	0.79 (0.69 – 0.91), p = 0.001	0.89 (0.70 – 1.12), p = 0.31
Non-fatal MI	0.84 (0.75 – 0.95), p = 0.005	0.76 (0.67 – 0.85), p < 0.001
Death from any cause	0.78 (0.69 – 0.89), p < 0.001	0.95 (0.78 – 1.16), p = 0.64
Stent thrombosis (definite or probable)	0.75 (0.59 – 0.95), p = 0.02	0.48 (0.36 – 0.64), p < 0.001
Non-CABG-related major bleeding (TIMI criteria)	1.25 (1.03 – 1.53), p = 0.03	1.32 (1.03 – 1.68), p = 0.03
Fatal bleeding	0.87 (0.48 – 1.59), p = 0.66	4.19 (1.58 – 11.11), p = 0.002
Intracranial bleeding	1.87 (0.98 – 3.58), p = 0.06	1.12 (0.58 – 2.15), p = 0.74

*The PLATO and TRITON trials compared respectively ticagrelor and prasugrel with clopidogrel in ACS patients. To this date, there is no randomised trial comparing ticagrelor with prasugrel in ACS patients. Further, the designs and the populations of these studies differ. Results of the PLATO trial are at 12 months whereas in the TRITON trial they are at 15 months.

ACS: Acute coronary syndrome; CABG: Coronary artery by-pass grafting; CI: Confidence interval; MI: Myocardial infarction.

In addition to its reduction in cardiovascular mortality, ticagrelor has several advantages. It can be administered in patients older than 75 years or with a history of stroke/TIA (transient ischemic attack) or with a weight < 60 kg without increase in bleedings [5,6]. Ticagrelor can also be prescribed before coronary angiography or even in patients previously treated with clopidogrel (unlike prasugrel). Thus, international guidelines recommend its use as first-line agent in association with low-dose aspirin without any restriction [7].

However, ticagrelor has several limitations restricting its prescription. The first one is economic: its cost is greater than that of clopidogrel (especially its generic versions), which limits its distribution in developing countries [8].

Consistent with the more intense platelet reactivity inhibition obtained with ticagrelor compared with clopidogrel, it is associated with an increase in the rate of non-CABG-related bleedings [2].

Surprisingly and for the first time since ticlodipine, an antiplatelet agent has significant extra-cardiac adverse side effects. Trials have shown that ticagrelor is associated with higher rates of dyspnea and bradycardia. They are also probably related to adenosine even if their mechanisms are not clearly understood [2,9]. Drug interactions require precautions: CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, atazanavir) should be avoided in patients treated with ticagrelor. Also, alteration of renal function and dyspnea seem to occur more frequently in patients treated with ticagrelor associated with angiotensin-receptor blocker [10].

Regarding ST-segment elevation myocardial infarction (STEMI) patients, a pre-defined sub-group analysis conducted by Steg et al. failed to show any superiority of ticagrelor over clopidogrel in this specific population regarding the primary end point composed of MI/stroke or cardiovascular death [11]. However, in the PLATO trial there was no interaction between the efficacy on the primary end point and the presentation which suggests that the lack of clinical significance in this sub-group is related to a lack of power.

Expert opinion

Ticagrelor is an excellent P2Y12 inhibitor and therefore should be used in combination with aspirin as first-line antiplatelet agents in ACS patients undergoing either invasive or non-invasive management. Controversy remains in STEMI patients that might benefit from prasugrel that met its composite primary end point of cardiovascular death, non-fatal MI or non-fatal stroke in the sub-group analysis of STEMI patients of the TRITON-TIMI 38 trial (Table 1) [12]. However, it should be acknowledged that when only primary PCI is taken into account the difference with clopidogrel in this sub-group is not significant (p = 0.3) similarly to ticagrelor.

Interestingly, in the PLATO trial non-CABG major bleeding events occurred in 4.5% of patients treated with ticagrelor whereas the rate of the thrombotic end points was 9.8% [2]. With the use of more potent antiplatelet agents, bleeding events are becoming more frequent and their rate tends to approach the rate of thrombotic events, which is reducing. Strategies to lower the risk of bleedings become crucial such as the use of radial access for PCI or the administration of bivalirudin rather than the association of glycoprotein IIb – IIIa inhibitors and heparin in STEMI patients. Given the increased risk of MI, stroke and deaths in bleeding patients under dual antiplatelet therapy, such strategies are mandatory and should be promoted [13].

Several questions remain unanswered: is it necessary to give a ticagrelor loading dose to ACS patients previously loaded with 600 mg of clopidogrel? Is it necessary to treat patients with ticagrelor during pre-hospital cares? Has ticagrelor pleiotropic effects? Is there any interaction between new oral anticoagulants and is their association with ticagrelor safe? Has the association of aspirin and ticagrelor any interest in patients having a history of MI? Several trials such as the PEGASUS TIMI-54 study are underway and will try to answer these important clinical issues.

In view of the results of the PLATO trial, ticagrelor has the potential to become the new gold standard of P2Y12 ADP receptor blockers for ACS.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.