Blockade of the P2Y₁₂-ADP receptor is critical in the care of acute coronary syndromes (ACS). Indeed, dual antiplatelet therapy (DAPT) is mandatory to prevent patients from ischemic recurrences (including stent thrombosis, myocardial infarction, and cardiovascular death) during these acute atherothrombotic events.¹ Clopidogrel remained the gold standard of P2Y₁₂-ADP receptor antagonists for several years and participated in the wide expansion of percutaneous coronary intervention (PCI) for revascularization.

In 2001, stent thrombosis continued to occur despite DAPT, leading investigators to suspect clopidogrel "resistance." In fact, biological studies showed that clopidogrel, which is a pro-drug with a short-lived active metabolite, had a mild potency, a slow onset of action, and a large inter-individual variability in its biological effects. These limitations were associated with adverse ischemic events including stent thrombosis.²

Since then, new P2Y₁₂-ADP receptor antagonists, such as ticagrelor and prasugrel, have been developed to overcome these limitations and further improve the clinical outcome of patients suffering from ACS.³ Ticagrelor is from a new class of drugs (cyclopentyl triazolo pyrimidine) that differs from thienopyridines. Unlike thienopyridines, it does not require hepatic biotransformation to become active; it has a reversible and original mechanism of action and was recently shown to exert off-target properties.²

Biological Efficacy and Antiplatelet Properties

The metabolism of ticagrelor contributes to its superiority over clopidogrel. Ticagrelor does not require biotransformation to be active. It has a significantly shorter delay of action, requiring only 1 hour to achieve maximal platelet reactivity inhibition compared with 6-12 hours for clopidogrel in stable patients.^4,5 Consistently, ticagrelor has much faster antiplatelet effects than clopidogrel in patients with ACSs.⁶ Beyond its quick onset of action, ticagrelor induces a more potent platelet reactivity inhibition in patients with ACS and has a very low inter-patient variability; the rate of high on-treatment platelet reactivity is around 3% in this clinical setting compared with 30-40% with clopidogrel.² In addition, ticagrelor has off-target effects, including an increase in adenosine plasma concentration, which has significant vasodilatatory properties.⁷ Another benefit compared with clopidogrel is that ticagrelor is a reversible P2Y₁₂-ADP receptor antagonist, which allows a quicker restoration of platelet function than thienopyridines. Indeed, platelet reactivity returns to normal within 3 days following ticagrelor removal compared with 5 days with clopidogrel.⁴ This property is of clinical importance in patients requiring surgery and/or experiencing bleeding.

Clinical Trials

The PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial tested the efficacy of ticagrelor 90 mg twice daily compared with clopidogrel standard therapy in non-ST-segment elevation ACS and ST-segment elevation myocardial infarction (STEMI). This trial randomized more than 18,000 patients with ACS who could be managed medically with PCI or surgically with coronary artery bypass graft surgery (CABG). Overall, and consistently in every major subgroup of patients (e.g., STEMI, non-ST-segment elevation ACS, patient intended for invasive management, medical management or undergoing CABG), ticagrelor was associated with a significant reduction in ischemic events. Consistent with its higher potency and superior pharmacodynamic profile, ticagrelor reduced the rates of myocardial infarction and stent thrombosis compared with clopidogrel. Of note, ticagrelor significantly reduced overall mortality compared with clopidogrel (hazard ratio: 0.78 (0.69-0.89); p < 0.01). Ticagrelor is the first P2Y₁₂-ADP receptor antagonist to exhibit such mortality benefit, which prompted the research of pleiotropic properties. In the PLATO trial, although the overall rate of major bleeding was similar between ticagrelor and clopidogrel, the rate of non-CABG-related major bleeding was increased in the ticagrelor group (2.8 vs. 2.2%; p = 0.03).⁸

Following this pivotal trial, investigators also aimed to assess the potential of a long-term therapy with ticagrelor for chronic treatment of patients with coronary disease. In the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trial, clopidogrel plus aspirin failed to prevent atherothrombotic events compared with aspirin alone in high-risk patients.⁹ The PEGASUS (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin) trial compared DAPT with aspirin plus ticagrelor to aspirin alone in patients with a history of myocardial infarction (>12 months before) and risk factors (i.e., age ≥ 65 years, diabetes mellitus requiring medication, a second prior spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction). There were 3 treatment groups: placebo, ticagrelor 60 mg bid, and ticagrelor 90 mg bid. Over 33 months of follow-up, both doses of ticagrelor, combined with aspirin, were superior to aspirin alone for preventing death, myocardial infarction, or stroke. Treatment with ticagrelor was associated with an increased risk of major Thrombolysis in Myocardial Infarction (TIMI) non-CABG-related bleeding. Of importance, the lower dose of ticagrelor had similar ischemic benefit but a reduced bleeding harm compared with the high dose. All-cause mortality was not significantly different between groups. This study identified a sub-group of patients at high risk of recurrent ischemic events that occurred more than 12 months after an initial myocardial infarction who could benefit from prolonged DAPT by aspirin and ticagrelor.¹⁰ Accordingly, the updated guidelines on the duration of DAPT suggest that selected patients identified according to the DAPT score may benefit from such prolonged ticagrelor therapy beyond 12 months following ACS.¹¹

Nonhemorrhagic Side Effects

In line with its original mechanism of action and metabolism, ticagrelor was associated with a higher rate of transient dyspnea in the PLATO and PEGASUS trials, which reinforced the hypothesis of off-target properties of the drug. This side effect was associated with a higher rate of drug discontinuation.^8,9

Pleiotropic Properties

The all-cause mortality benefit observed with ticagrelor in the PLATO trial and the side effect prompted the hypothesis of pleiotropic effects of ticagrelor beyond its antiplatelet properties. Consistently in ACS we have observed that ticagrelor—unlike clopidogrel—was associated with a biological property over the adenosine compartment. Through an inhibition of adenosine recapture by red blood cells, ticagrelor increases adenosine plasma concentration.⁷ Increased adenosine plasma concentration translates to further platelet inhibition and arterial vasodilatation and may reduce reperfusion injury.^12,13 Adenosine may also be involved in the occurrence of dyspnea.

Pretreatment With Ticagrelor in ACS

Administration of oral P2Y₁₂ inhibitors prior to coronary angiography has long been the gold standard in patients with ACS. The aim of such a strategy was to allow stent implantation to be performed at a time when platelet activation was reduced to prevent ischemic complications and avoid early stent thrombosis. Pretreatment would also reduce pre-PCI ischemic events by reducing thrombotic burden. Consistently in the PLATO trial, clopidogrel and ticagrelor were administered before coronary angiography in non-ST-segment elevation ACS.⁸

Non-ST-Segment Elevation ACS

The widely debated ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial suggested that pretreatment of patients with ACS with prasugrel is not effective in reducing ischemic events and could be harmful due to the increased risk of bleeding compared with the administration of a loading dose at the time of PCI.¹⁴ Thus, international guidelines discourage pretreatment with prasugrel in non-ST-segment elevation ACS.³ A recent meta-analysis confirmed the lack of ischemic benefit of clopidogrel pretreatment and its potential harm.¹⁵ To date, no trial has investigated the potential risk/benefit ratio of ticagrelor pretreatment in this setting.

STEMI

ATLANTIC (A 30 Day Study to Evaluate Efficacy and Safety of Pre-hospital vs. In-hospital Initiation of Ticagrelor Therapy in STEMI Patients Planned for PCI) was a randomized controlled trial assessing the benefit of pretreatment with ticagrelor compared with placebo in STEMI patients. Its co-primary endpoints were ST-segment resolution on admission or TIMI III flow before PCI. ATLANTIC did not reach its primary endpoint. The lack of superiority of pretreatment may be related to the small difference in the timing of the loading dose, which differed only 30 minutes between the 2 groups.¹⁶ Of interest, unlike the ACCOAST trial, pretreatment was not associated with increased bleeding events.

Conclusion

Ticagrelor is a faster and more potent P2Y₁₂ inhibitor that demonstrated a significant clinical benefit over clopidogrel in ACS. It is therefore recommended as a first-line agent over clopidogrel in ACS and can be used in high-risk PCI in patients with stable angina. The benefit of ticagrelor is independent of the therapeutic strategy chosen: medical, invasive, or surgical. In addition, in selected patients with a history of myocardial infarction, beyond the first year of DAPT, a reduced dose of ticagrelor seems to prevent atherothrombotic events, which further expands the benefit of DAPT. Beyond ticagrelor's antiplatelet properties, pleiotropic effects may explain the results of the pivotal clinical trial and suggest a mortality benefit of the drug over clopidogrel.

References

1. Mehta SR, Yusuf S, Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study Investigators. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J 2000;21:2033-41.
2. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013;62:2261-73.
3. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016 ;37:267-315.
4. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120:2577-85.
5. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005;111:2560-4.
6. Storey RF, Angiolillo DJ, Patil SB, et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010;56:1456-62.
7. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63:872-7
8. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
9. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17.
10. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.
11. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016 Mar 23 [Epub ahead of print].
12. Nylander S, Femia EA, Scavone M, et al. Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism. J Thromb Haemost 2013;11:1867-76.
13. Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y. Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol 2015;35:1805-14.
14. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013;369:999-1010.
15. Bellemain-Appaix A, Kerneis M, O'Connor SA, et al. Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis. BMJ 2014;349:g6269
16. Montalescot G, van't Hof AW, Lapostolle F, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014;371:1016-27.

Keywords: Acute Coronary Syndrome, Adenosine, Angina, Stable, Aspirin, Biotransformation, Blood Platelets, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Diabetes Mellitus, Dyspnea, Erythrocytes, Myocardial Infarction, Organoplatinum Compounds, Percutaneous Coronary Intervention, Platelet Activation, Platelet Aggregation Inhibitors, Prodrugs, Purinergic P2Y Receptor Antagonists, Pyrimidines, Receptors, Purinergic P2, Reperfusion Injury, Risk Factors, Stroke, Stents, Thienopyridines, Thrombosis, Ticlopidine, Vasodilation

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