Antiplatelet Therapy with Prasugrel and Ticagrelor in the Treatment of Patients with Acute Coronary Syndrome

    Authors

    • Zvonimir Ostojić — Klinički bolnički centar Zagreb, Zagreb, Hrvatska

    Abstract

    Dual antiplatelet therapy (DAPT) forms the basis for the treatment of all patients undergoing percutaneous coronary intervention (PCI) and patients who suffered acute coronary syndrome (ACS). Prasugrel and ticagrelor are potent P2Y12 receptor inhibitors that have demonstrated their superiority in patients with ACS in comparison with clopidogrel in multiple clinical trials. In a recent randomized clinical trial called ISAR REACT 5, prasugrel provided a statistically significant reduction in the rate of ischemic outcomes without an increase in bleeding complications, in comparison with ticagrelor. Similar results were also presented in a subsequent meta-analysis. Considering the above and according to current guidelines for non-ST elevation ACS, prasugrel is the P2Y12 inhibitor of choice in the treatment of patients undergoing PCI. On the other hand, ticagrelor is the treatment of choice in cases when prasugrel is contraindicated. However, in some patient populations (patients older than 75 and weighing less than 60 kg) and clinical scenarios (delayed invasive treatment), no clear recommendations can be made regarding therapy or treatment of choice due to inadequate evidence. Both agents are also indicated in situations when prolonged DAPT is required, although ticagrelor is the preferred choice. Finally, randomized studies on P2Y12 inhibitor monotherapy after 1 to 3 months of DAPT following PCI indicate a reduction in bleeding complications, but without any significant increase in ischemic complications, compared with classic DAPT. However, additional research is required in this area before introducing any changes to everyday clinical practice.

    Keywords

    prasugrel, ticagrelor, dual antiplatelet therapy, acute coronary syndrome

    DOI

    https://doi.org/10.15836/ccar2021.269

    Full Text

    ## Introduction Dual antiplatelet therapy (DAPT) forms the basis for the treatment of all patients undergoing percutaneous coronary intervention (PCI) and patients who suffered acute coronary syndrome (ACS) (1-3). Multiple clinical trials consistently show that one year of DAPT, consisting of aspirin and a P2Y12 receptor inhibitor, lowers the risk of a future atherothrombotic event after ACS (4-7). Furthermore, therapy with more potent P2Y12 inhibitors, prasugrel or ticagrelor, provides better protection from ischemic events but with a higher frequency of bleeding complications than with clopidogrel (5, 6). This is why prasugrel and ticagrelor are the P2Y12 inhibitors of choice when treating patients without a high risk of bleeding with acute ST elevation myocardial infarction (STEMI) and non-ST elevation ACS (2, 3). ## Prasugrel Prasugrel is a thienopyridine P2Y12 receptor inhibitor with a rapid onset of action (8, 9). Just like clopidogrel, prasugrel requires conversion into active substance by intestinal esterase and by cytochrome P-450 before it can demonstrate its antiplatelet effect (10). Unlike with clopidogrel, this activation happens significantly sooner, already within 15 minutes. Moreover, prasugrel’s activation path through cytochrome P-450 is different from that of clopidogrel and is significantly less dependent on concomitant therapy and genetic variants of the cytochrome (9). Because of the above, prasugrel, when compared with clopidogrel, leads to more consistent and more reliable inhibition of platelet aggregation. TRITON TIMI 38 was the first large, randomized, double-blind clinical study to compare prasugrel and clopidogrel (5). The study included patients with ACS, 99% of whom had undergone PCI. In the study, therapy with prasugrel led to a reduction in overall major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke (9.9% vs. 12.1%, hazard ratio (HR) 0.81, 95% CI 0.73-0.90, p 12 receptor inhibitor with a rapid onset of action of 30 minutes (8, 16). Unlike prasugrel, ticagrelor does not require conversion to active substance. In the PLATO registration study, there was a significant reduction in MACE (9.8% vs. 11.7%; HR 0.84; 95% CI 0.77-0.92, p 12 inhibitors (7). On the other hand, ticagrelor and prasugrel lead to a significant reduction in overall mortality compared with clopidogrel. In terms of numbers, prasugrel had fewer fatal outcomes than ticagrelor, but without statistical significance (7). Even after one year of follow-up, no statistically significant difference was reported in bleeding complications (7). Considering all of the above, both P2Y12 receptor inhibitors, prasugrel and ticagrelor, are appropriate options for treating patients with ACS without high risk of bleeding. Nevertheless, considering the ISAR REACT 5 study and the meta-analysis, prasugrel is preferred to ticagrelor. This has also been recognized in the current guidelines for the treatment of non-ST elevation ACS, and similar recommendations can be expected in the future guidelines for STEMI (3). In addition, prasugrel is the treatment of choice for patients (undergoing PCI) who were initially treated with ticagrelor or who developed non-exertional dyspnea. Specifically, this adverse effect persists in approximately 4% of patients on ticagrelor after 7 days of therapy (8, 19). On the other hand, the advantages of prasugrel are not as clear in certain patient populations and clinical scenarios. This primarily refers to patients who suffered a stroke, in whom prasugrel is contraindicated, i.e. in whom ticagrelor is the only right option (if the estimated total bleeding risk is not high). Similarly, in patients with ACS in whom medication treatment is intended and who do not have high bleeding risk, ticagrelor is a better option than clopidogrel. In addition, ticagrelor is also preferred in clinical scenarios when delayed invasive diagnostics or treatment is planned. Namely, guidelines for non-ST elevation ACS no longer recommend using P2Y12 inhibitors without being familiar with coronary anatomy if early invasive treatment is planned, defined as occurring within 24 hours of diagnosis (3). It should be noted that the average time to PCI was 4.3 hours in ACCOAST (13). Nevertheless, the guidelines themselves include the option of using P2Y12 inhibitors in situations when the risk of bleeding is not high and early invasive treatment is not planned (3). In such situations, according to the results of these studies, ticagrelor is preferred to clopidogrel. Finally, the question remains what to do with the group of patients who are candidates for a lower dose of prasugrel of 5 mg (older than 75 and below 60 kg). As stated previously, although the efficacy of this dose has been described in pharmacokinetic investigations, there is no clear clinical evidence of the superiority of prasugrel over ticagrelor in these patient groups. In case of prolonged DAPT (after one year), guidelines for treating non-ST elevation ACS recommend prolonged DAPT with a relatively strong level IIa recommendation (evidence level A) in patients with an estimated high risk of ischemic incidents and low risk of bleeding and provide a level IIb (evidence level A) recommendation for patients with moderate risk of ischemic events and low risk of bleeding (3). In such clinical cases, the recommended first treatment option is ticagrelor at a reduced dose (2 × 60 mg) based on the previously described PEGASUS-TIMI 54 study, while prasugrel (or clopidogrel) are second-choice agents based on the DAPT study (3, 17). ## Prasugrel and ticagrelor as monotherapy Thanks to advancements in stent design and with the goal of reducing primarily bleeding complications of DAPT after PCI, studies have been conducted with earlier discontinuation of P2Y12 inhibitors and continued monotherapy with aspirin (20, 21). A similar approach has been in development in recent years, but it involves discontinuing therapy with aspirin after the initial 1-3 months of DAPT and continuing therapy with a P2Y12 inhibitor (22). The premise behind this approach is that, besides inhibiting platelet aggregation, aspirin has a harmful effect on the gastrointestinal mucosa as a cyclooxygenase 1 inhibitor; gastrointestinal bleeding being the most common cause of bleeding complications (20). Furthermore, pharmacodynamics studies demonstrated limited influence of the anti-aggregation effect of aspirin if the patient was on a potent P2Y12 inhibitor (20, 23, 24). Finally, the risk of stent thrombosis with a modern DES is highest during the first month (25-29). Five randomized studies have been published to date in which DAPT was discontinued after 1-3 months post PCI, which involved discontinuing therapy with aspirin and continuing therapy with a P2Y12 inhibitor (three studies involved ticagrelor and two involved various P2Y12 inhibitors, primarily clopidogrel) (30-34). Most of these studies, as well as two meta-analyses, identified a reduction in serious bleeding complications from 31 to 71% in the “short” DAPT group (25, 30-35). No study found statistically significant differences in ischemic complications, MACE, or mortality. The results were consistent regardless of the clinical circumstances of the PCI – acute or chronic coronary syndrome, high-risk patients, or complex PCI (26, 36-38). Based on these results, guidelines for treating non-ST elevation ACS already allow using DAPT (aspirin and ticagrelor) for 3 months, after which monotherapy with ticagrelor is continued at a full dose in patients with low risk of bleeding (3). The results of the ASET pilot study were recently published (39). ASET was a multicentric, observational study involving 201 subjects undergoing non-complicated elective PCI (39). On the day of their PCI, the subjects were given their last dose of standard therapy with DAPT (clopidogrel and aspirin) which was then discontinued and replaced by prasugrel monotherapy for the next 3 months of the follow-up period. During this time, one case (0.5%) of a combined ischemic and bleeding outcome was reported (39). Based on these results, plans are being made for a prospective study in which all the patients will exclusively receive prasugrel monotherapy during the study and the one-year follow-up. ## Conclusion Potent P2Y12 inhibitors, prasugrel or ticagrelor, are an integral part of DAPT in patients with ACS who underwent PCI and who do not have a high risk of bleeding complications. According to present studies, the protection provided by prasugrel therapy compared with ticagrelor is greater than the potential ischemic outcomes in selected groups of patients, without increased risk of bleeding, and is therefore the first treatment of choice. On the other hand, ticagrelor is the treatment of choice in patients with ACS treated with medication. In spite of the promising results of the studies involving reduced 3-month DAPT followed by continued therapy with a P2Y12 inhibitor, additional studies are required, primarily in patients with ACS, before introducing any changes to the current clinical practice.

    Literature

    1. Capodanno D, Alfonso F, Levine GN, Valgimigli M, Angiolillo DJ. ACC/AHA Versus ESC Guidelines on Dual Antiplatelet Therapy: JACC Guideline Comparison. J Am Coll Cardiol. 2018 December 11;72 23 Pt A:2915–31. https://doi.org/10.1016/j.jacc.2018.09.057
    2. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018 January 7;39(2):119–77. https://doi.org/10.1093/eurheartj/ehx393
    3. Collet JP, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021 April 7;42(14):1289–367. https://doi.org/10.1093/eurheartj/ehaa575
    4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 August 16;345(7):494–502. https://doi.org/10.1056/NEJMoa010746
    5. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 November 15;357(20):2001–15. https://doi.org/10.1056/NEJMoa0706482
    6. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 September 10;361(11):1045–57. https://doi.org/10.1056/NEJMoa0904327
    7. Baldetti L, Melillo F, Moroni F, Gallone G, Pagnesi M, Venuti A, et al. Meta-Analysis Comparing P2Y12 Inhibitors in Acute Coronary Syndrome. Am J Cardiol. 2020 June 15;125(12):1815–22. https://doi.org/10.1016/j.amjcard.2020.03.019
    8. Kamran H, Jneid H, Kayani WT, Virani SS, Levine GN, Nambi V, et al. Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review. JAMA. 2021 April 20;325(15):1545–55. https://doi.org/10.1001/jama.2021.0716
    9. Norgard NB, Abu-Fadel M. Comparison of prasugrel and clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Vasc Health Risk Manag. 2009;5:873–82. https://doi.org/10.2147/VHRM.S5699
    10. Wiviott SD, Antman EM, Braunwald E. Prasugrel. Circulation. 2010 July 27;122(4):394–403. https://doi.org/10.1161/CIRCULATIONAHA.109.921502
    11. Riesmeyer JS, Salazar DE, Weerakkody GJ, Ni L, Wrishko RE, Ernest CS, et al. Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy. J Clin Pharmacol. 2012 June;52(6):789–97. https://doi.org/10.1177/0091270011406280
    12. Erlinge D, Ten Berg J, Foley D, Angiolillo DJ, Wagner H, Brown PB, et al. Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial. J Am Coll Cardiol. 2012 November 13;60(20):2032–40. https://doi.org/10.1016/j.jacc.2012.08.964
    13. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al. ACCOAST Investigators. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013 September 12;369(11):999–1010. https://doi.org/10.1056/NEJMoa1308075
    14. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012 October 4;367(14):1297–309. https://doi.org/10.1056/NEJMoa1205512
    15. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014 December 4;371(23):2155–66. https://doi.org/10.1056/NEJMoa1409312
    16. Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014 October;34(10):1077–90. https://doi.org/10.1002/phar.1477
    17. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015 May 7;372(19):1791–800. https://doi.org/10.1056/NEJMoa1500857
    18. Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, et al. ISAR-REACT 5 Trial Investigators. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2019 October 17;381(16):1524–34. https://doi.org/10.1056/NEJMoa1908973
    19. Parodi G, Storey RF. Dyspnoea management in acute coronary syndrome patients treated with ticagrelor. Eur Heart J Acute Cardiovasc Care. 2015 December;4(6):555–60. https://doi.org/10.1177/2048872614554108
    20. Capodanno D, Angiolillo DJ. When Less Becomes More: Insights on the Pharmacodynamic Effects of Aspirin Withdrawal in Patients With Potent Platelet P2Y12 Inhibition Induced by Ticagrelor. J Am Heart Assoc. 2020 December 15;9(24):e019432. https://doi.org/10.1161/JAHA.120.019432
    21. Schulz-Schüpke S, Byrne RA, Ten Berg JM, Neumann FJ, Han Y, Adriaenssens T, et al. Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J. 2015 May 21;36(20):1252–63. https://doi.org/10.1093/eurheartj/ehu523
    22. Capodanno D, Mehran R, Valgimigli M, Baber U, Windecker S, Vranckx P, et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol. 2018 August;15(8):480–96. https://doi.org/10.1038/s41569-018-0049-1
    23. Armstrong PC, Leadbeater PD, Chan MV, Kirkby NS, Jakubowski JA, Mitchell JA, et al. In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J Thromb Haemost. 2011 March;9(3):552–61. https://doi.org/10.1111/j.1538-7836.2010.04160.x
    24. Johnson TW, Baos S, Collett L, Hutchinson JL, Nkau M, Molina M, et al. Pharmacodynamic Comparison of Ticagrelor Monotherapy Versus Ticagrelor and Aspirin in Patients After Percutaneous Coronary Intervention: The TEMPLATE (Ticagrelor Monotherapy and Platelet Reactivity) Randomized Controlled Trial. J Am Heart Assoc. 2020 December 15;9(24):e016495. https://doi.org/10.1161/JAHA.120.016495
    25. Giacoppo D, Matsuda Y, Fovino LN, D’Amico G, Gargiulo G, Byrne RA, et al. Short dual antiplatelet therapy followed by P2Y12 inhibitor monotherapy vs. prolonged dual antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents: a systematic review and meta-analysis of randomized clinical trials. Eur Heart J. 2021 January 21;42(4):308–19. https://doi.org/10.1093/eurheartj/ehaa739
    26. Galli M, Capodanno D, Andreotti F, Crea F, Angiolillo DJ. Safety and efficacy of P2Y12 inhibitor monotherapy in patients undergoing percutaneous coronary interventions. Expert Opin Drug Saf. 2021 January;20(1):9–21. https://doi.org/10.1080/14740338.2021.1850691
    27. Benenati S, Crimi G, Canale C, Pescetelli F, De Marzo V, Vergallo R, et al. Duration of dual antiplatelet therapy and subsequent monotherapy type in patients undergoing drug eluting stent implantation: a network Meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2020 Nov 2:pvaa127. https://doi.org/10.1093/ehjcvp/pvaa127
    28. Gargiulo G, Valgimigli M, Capodanno D, Bittl JA. State of the art: duration of dual antiplatelet therapy after percutaneous coronary intervention and coronary stent implantation - past, present and future perspectives. EuroIntervention. 2017 August 25;13(6):717–33. https://doi.org/10.4244/EIJ-D-17-00468
    29. Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014. Eur Heart J. 2015 December 14;36(47):3320–31. https://doi.org/10.1093/eurheartj/ehv511
    30. Vranckx P, Valgimigli M, Jüni P, Hamm C, Steg PG, Heg D, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018 September 15;392(10151):940–9. https://doi.org/10.1016/S0140-6736(18)31858-0
    31. Hahn JY, Song YB, Oh JH, Chun WJ, Park YH, Jang WJ, et al. Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial. JAMA. 2019 June 25;321(24):2428–37. https://doi.org/10.1001/jama.2019.8146
    32. Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019 June 25;321(24):2414–27. https://doi.org/10.1001/jama.2019.8145
    33. Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019 November 21;381(21):2032–42. https://doi.org/10.1056/NEJMoa1908419
    34. Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, et al. Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020 June 16;323(23):2407–16. https://doi.org/10.1001/jama.2020.7580
    35. O’Donoghue ML, Murphy SA, Sabatine MS. The Safety and Efficacy of Aspirin Discontinuation on a Background of a P2Y12 Inhibitor in Patients After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis. Circulation. 2020 August 11;142(6):538–45. https://doi.org/10.1161/CIRCULATIONAHA.120.046251
    36. Baber U, Dangas G, Angiolillo DJ, Cohen DJ, Sharma SK, Nicolas J, et al. Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS. Eur Heart J. 2020 October 1;41(37):3533–45. https://doi.org/10.1093/eurheartj/ehaa670
    37. Angiolillo DJ, Baber U, Sartori S, Briguori C, Dangas G, Cohen DJ, et al. Ticagrelor With or Without Aspirin in High-Risk Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention. J Am Coll Cardiol. 2020 May 19;75(19):2403–13. https://doi.org/10.1016/j.jacc.2020.03.008
    38. Dangas G, Baber U, Sharma S, Giustino G, Mehta S, Cohen DJ, et al. Ticagrelor With or Without Aspirin After Complex PCI. J Am Coll Cardiol. 2020 May 19;75(19):2414–24. https://doi.org/10.1016/j.jacc.2020.03.011
    39. Kogame N, Guimarães PO, Modolo R, De Martino F, Tinoco J, Ribeiro EE, et al. Aspirin-Free Prasugrel Monotherapy Following Coronary Artery Stenting in Patients With Stable CAD: The ASET Pilot Study. JACC Cardiovasc Interv. 2020 October 12;13(19):2251–62. https://doi.org/10.1016/j.jcin.2020.06.023
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    Antiplatelet Therapy with Prasugrel and Ticagrelor in the Treatment of Patients with Acute Coronary Syndrome

    Professional Article
    Issue7-8
    Published
    Pages269-275
    PDF via DOIhttps://doi.org/10.15836/ccar2021.269
    prasugrel
    ticagrelor
    dual antiplatelet therapy
    acute coronary syndrome

    Authors

    Zvonimir Ostojić*Klinički bolnički centar Zagreb, Zagreb, Hrvatska

    *Correspondence email: ostojiczvonimir@gmail.com

    Abstract

    Dual antiplatelet therapy (DAPT) forms the basis for the treatment of all patients undergoing percutaneous coronary intervention (PCI) and patients who suffered acute coronary syndrome (ACS). Prasugrel and ticagrelor are potent P2Y12 receptor inhibitors that have demonstrated their superiority in patients with ACS in comparison with clopidogrel in multiple clinical trials. In a recent randomized clinical trial called ISAR REACT 5, prasugrel provided a statistically significant reduction in the rate of ischemic outcomes without an increase in bleeding complications, in comparison with ticagrelor. Similar results were also presented in a subsequent meta-analysis. Considering the above and according to current guidelines for non-ST elevation ACS, prasugrel is the P2Y12 inhibitor of choice in the treatment of patients undergoing PCI. On the other hand, ticagrelor is the treatment of choice in cases when prasugrel is contraindicated. However, in some patient populations (patients older than 75 and weighing less than 60 kg) and clinical scenarios (delayed invasive treatment), no clear recommendations can be made regarding therapy or treatment of choice due to inadequate evidence. Both agents are also indicated in situations when prolonged DAPT is required, although ticagrelor is the preferred choice. Finally, randomized studies on P2Y12 inhibitor monotherapy after 1 to 3 months of DAPT following PCI indicate a reduction in bleeding complications, but without any significant increase in ischemic complications, compared with classic DAPT. However, additional research is required in this area before introducing any changes to everyday clinical practice.

    Full Text

    Introduction

    Dual antiplatelet therapy (DAPT) forms the basis for the treatment of all patients undergoing percutaneous coronary intervention (PCI) and patients who suffered acute coronary syndrome (ACS) (1–3). Multiple clinical trials consistently show that one year of DAPT, consisting of aspirin and a P2Y12 receptor inhibitor, lowers the risk of a future atherothrombotic event after ACS (4–7). Furthermore, therapy with more potent P2Y12 inhibitors, prasugrel or ticagrelor, provides better protection from ischemic events but with a higher frequency of bleeding complications than with clopidogrel (5, 6). This is why prasugrel and ticagrelor are the P2Y12 inhibitors of choice when treating patients without a high risk of bleeding with acute ST elevation myocardial infarction (STEMI) and non-ST elevation ACS (2, 3).

    Prasugrel

    Prasugrel is a thienopyridine P2Y12 receptor inhibitor with a rapid onset of action (8, 9). Just like clopidogrel, prasugrel requires conversion into active substance by intestinal esterase and by cytochrome P-450 before it can demonstrate its antiplatelet effect (10). Unlike with clopidogrel, this activation happens significantly sooner, already within 15 minutes. Moreover, prasugrel’s activation path through cytochrome P-450 is different from that of clopidogrel and is significantly less dependent on concomitant therapy and genetic variants of the cytochrome (9). Because of the above, prasugrel, when compared with clopidogrel, leads to more consistent and more reliable inhibition of platelet aggregation.

    TRITON TIMI 38 was the first large, randomized, double-blind clinical study to compare prasugrel and clopidogrel (5). The study included patients with ACS, 99% of whom had undergone PCI. In the study, therapy with prasugrel led to a reduction in overall major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke (9.9% vs. 12.1%, hazard ratio (HR) 0.81, 95% CI 0.73-0.90, p < 0.001) (5). On the other hand, prasugrel treatment also caused a higher incidence of bleeding complications that were not associated with cardiac surgical revascularization (2.4% vs. 1.8%, HR 1.32, 95% CI 1.03-1.68, p = 0.03) (5). In subsequent subanalyses, three groups of patients with especially high risk of bleeding were identified: 1) patients with a history of stroke, 2) patients older than 75 years of age, 3) patients with body weight under 60 kg (5). In accordance with the above and under current clinical recommendations, prasugrel is contraindicated in patients with a history of stroke and transient ischemic attack, whereas in patients older than 75 and patients with body weight under 60 kg it is advisable to reduce the maintenance dose by half, from the standard 10 mg to 5 mg (1, 3). It should be noted that the above-mentioned recommendations concerning dose reduction are the result of pharmacokinetic studies, i.e. that clinical efficacy has not been confirmed in a randomized clinical study (11, 12). The ACCOAST clinical study, which included patients with non-ST elevation ACS, showed that using prasugrel before identifying coronary anatomy had no effect on the clinical or angiographic outcomes compared with the group of patients in whom the loading dose of prasugrel (60 mg) was administered after coronarography (13). On the other hand, patients in whom prasugrel was administered before coronarography (immediately after diagnosing ACS) had a significantly higher frequency of bleeding (HR, 1.90; 95% CI, 1.19 to 3.02; p = 0.006) (13). Based on this, prasugrel is indicated in patients with non-ST elevation ACS only after identifying coronary pathology or after deciding to perform PCI (3). Considering that the TRILOGY-ACS study, which included patients with ACS who had not undergone revascularization, found no significant reduction in MACE between clopidogrel and prasugrel, therapy with prasugrel is not indicated if PCI is not planned (14). Prasugrel therapy as a part of DAPT, can be continued even after one year, based on the results of the DAPT study (15). In it, out of almost 10.000 subjects in total, 32% had ACS, and after one year of DAPT (if they were able to tolerate it without significant adverse effects), they were randomized to continue treatment with either clopidogrel or prasugrel with aspirin or just aspirin with placebo (15). The results in the overall population confirmed statistically significantly lower incidence of stent thrombosis and myocardial infarction, but with a higher risk of bleeding and statistically borderline significantly higher overall mortality in the group receiving prolonged DAPT. After subgroup analysis, patients who had suffered ACS benefited more from the prolonged DAPT (15).

    Ticagrelor

    Ticagrelor is a non-thienopyridine, direct, reversible P2Y12 receptor inhibitor with a rapid onset of action of 30 minutes (8, 16). Unlike prasugrel, ticagrelor does not require conversion to active substance. In the PLATO registration study, there was a significant reduction in MACE (9.8% vs. 11.7%; HR 0.84; 95% CI 0.77-0.92, p < 0.001) and overall mortality as a separate outcome (HR 0.78; 95% CI 0.69-0.91, p < 0.001) with ticagrelor compared with clopidogrel (6). The group of patients treated with ticagrelor had a higher frequency of bleeding not associated with cardiac surgical revascularization (4.5% vs. 3.8%, p = 0.03), but there was no statistically significant difference in major hemorrhages (6). The study included patients regardless of which ACS treatment method was used (invasive or conservative), which is why ticagrelor is also indicated in cases where only medication therapy is used (1, 6). PEGASUS-TIMI 54 was another ticagrelor study with a significant influence on clinical practice, where over 21,000 patients with a history of myocardial infarction were randomized to receive: 1) ticagrelor at full dosage (2 × 90 mg), 2) ticagrelor at reduced dosage (2 × 60 mg) or 3) placebo (17). All patients were receiving ongoing therapy with aspirin. After three years of follow-up, a significant reduction in MACE was reported in both groups treated with ticagrelor (7.85% vs. 7.77% vs. 9.04%; HR 0.85, 95% CI 0.75-0.96 and 0.84, 95% CI 0.74-0.95) (17). Moreover, major hemorrhage incidence was significantly higher in the ticagrelor groups, without any differences in fatal or intracranial hemorrhage (17). Based on this study, current guidelines state that ticagrelor at 2 × 60 mg can potentially be continued in selected patients post ACS after one year of “classic” DAPT (3).

    It should be noted that patients who were considered to have high risk of bleeding were excluded in advance from all of the above-mentioned studies for both agents.

    Prasugrel vs. ticagrelor

    ISAR REACT 5 is the largest (over 4.000 patients) randomized study to date to directly compare prasugrel and ticagrelor in patients with ACS scheduled for intervention treatment (18). Subjects presenting with STEMI were immediately treated with the saturation dose for both agents (ticagrelor 180 mg, prasugrel 60 mg). If their initial diagnosis was non-ST elevation ACS, they were immediately treated with a saturation dose of ticagrelor, while prasugrel was administered only after coronarography (in line with the recommendations for administering these medications) (18). This generated the hypothesis that ticagrelor (due to its earlier administration) would be superior to prasugrel in MACE after one year. Contrary to the hypothesis, the results showed a clear reduction in MACE in the prasugrel group (6.9% vs. 9.3%, HR 1.36, 95% CI 1.09-1.70, p = 0.006) without any significant differences in bleeding complications (18). Patients with a history of stroke were excluded from the study (since prasugrel is contraindicated in these patients), while patients above the age of 75 (approximately 24% in both groups) and those with body weight below 60 kg (approximately 5% in both groups) were given a low dose of prasugrel of 5 mg (18). A subanalysis of these subgroups suggested the superiority of prasugrel (which is in line with the main results), but without statistical significance (18). A recently published meta-analysis of over 145,000 patients from a total of 14 randomized studies or large prospective registries compared prasugrel, ticagrelor, and clopidogrel in ACS (7). The results of this meta-analysis indicated that prasugrel was superior to ticagrelor and clopidogrel in reducing MACE and overall mortality after 30 days, while ticagrelor reduced overall mortality in comparison with clopidogrel (7). In addition, prasugrel significantly reduced the incidence of stent thrombosis, but without a significant difference in the incidence of myocardial infarction in comparison with ticagrelor. There were no statistically significant differences in bleeding after 30 days of follow-up. However, after one year there were no differences in MACE among the three studied P2Y12 inhibitors (7). On the other hand, ticagrelor and prasugrel lead to a significant reduction in overall mortality compared with clopidogrel. In terms of numbers, prasugrel had fewer fatal outcomes than ticagrelor, but without statistical significance (7). Even after one year of follow-up, no statistically significant difference was reported in bleeding complications (7).

    Considering all of the above, both P2Y12 receptor inhibitors, prasugrel and ticagrelor, are appropriate options for treating patients with ACS without high risk of bleeding. Nevertheless, considering the ISAR REACT 5 study and the meta-analysis, prasugrel is preferred to ticagrelor. This has also been recognized in the current guidelines for the treatment of non-ST elevation ACS, and similar recommendations can be expected in the future guidelines for STEMI (3). In addition, prasugrel is the treatment of choice for patients (undergoing PCI) who were initially treated with ticagrelor or who developed non-exertional dyspnea. Specifically, this adverse effect persists in approximately 4% of patients on ticagrelor after 7 days of therapy (8, 19). On the other hand, the advantages of prasugrel are not as clear in certain patient populations and clinical scenarios. This primarily refers to patients who suffered a stroke, in whom prasugrel is contraindicated, i.e. in whom ticagrelor is the only right option (if the estimated total bleeding risk is not high). Similarly, in patients with ACS in whom medication treatment is intended and who do not have high bleeding risk, ticagrelor is a better option than clopidogrel. In addition, ticagrelor is also preferred in clinical scenarios when delayed invasive diagnostics or treatment is planned. Namely, guidelines for non-ST elevation ACS no longer recommend using P2Y12 inhibitors without being familiar with coronary anatomy if early invasive treatment is planned, defined as occurring within 24 hours of diagnosis (3). It should be noted that the average time to PCI was 4.3 hours in ACCOAST (13). Nevertheless, the guidelines themselves include the option of using P2Y12 inhibitors in situations when the risk of bleeding is not high and early invasive treatment is not planned (3). In such situations, according to the results of these studies, ticagrelor is preferred to clopidogrel. Finally, the question remains what to do with the group of patients who are candidates for a lower dose of prasugrel of 5 mg (older than 75 and below 60 kg). As stated previously, although the efficacy of this dose has been described in pharmacokinetic investigations, there is no clear clinical evidence of the superiority of prasugrel over ticagrelor in these patient groups. In case of prolonged DAPT (after one year), guidelines for treating non-ST elevation ACS recommend prolonged DAPT with a relatively strong level IIa recommendation (evidence level A) in patients with an estimated high risk of ischemic incidents and low risk of bleeding and provide a level IIb (evidence level A) recommendation for patients with moderate risk of ischemic events and low risk of bleeding (3). In such clinical cases, the recommended first treatment option is ticagrelor at a reduced dose (2 × 60 mg) based on the previously described PEGASUS-TIMI 54 study, while prasugrel (or clopidogrel) are second-choice agents based on the DAPT study (3, 17).

    Prasugrel and ticagrelor as monotherapy

    Thanks to advancements in stent design and with the goal of reducing primarily bleeding complications of DAPT after PCI, studies have been conducted with earlier discontinuation of P2Y12 inhibitors and continued monotherapy with aspirin (20, 21). A similar approach has been in development in recent years, but it involves discontinuing therapy with aspirin after the initial 1-3 months of DAPT and continuing therapy with a P2Y12 inhibitor (22). The premise behind this approach is that, besides inhibiting platelet aggregation, aspirin has a harmful effect on the gastrointestinal mucosa as a cyclooxygenase 1 inhibitor; gastrointestinal bleeding being the most common cause of bleeding complications (20). Furthermore, pharmacodynamics studies demonstrated limited influence of the anti-aggregation effect of aspirin if the patient was on a potent P2Y12 inhibitor (20, 23, 24). Finally, the risk of stent thrombosis with a modern DES is highest during the first month (25–29).

    Five randomized studies have been published to date in which DAPT was discontinued after 1-3 months post PCI, which involved discontinuing therapy with aspirin and continuing therapy with a P2Y12 inhibitor (three studies involved ticagrelor and two involved various P2Y12 inhibitors, primarily clopidogrel) (30–34). Most of these studies, as well as two meta-analyses, identified a reduction in serious bleeding complications from 31 to 71% in the “short” DAPT group (25, 30–35). No study found statistically significant differences in ischemic complications, MACE, or mortality. The results were consistent regardless of the clinical circumstances of the PCI – acute or chronic coronary syndrome, high-risk patients, or complex PCI (26, 36–38). Based on these results, guidelines for treating non-ST elevation ACS already allow using DAPT (aspirin and ticagrelor) for 3 months, after which monotherapy with ticagrelor is continued at a full dose in patients with low risk of bleeding (3).

    The results of the ASET pilot study were recently published (39). ASET was a multicentric, observational study involving 201 subjects undergoing non-complicated elective PCI (39). On the day of their PCI, the subjects were given their last dose of standard therapy with DAPT (clopidogrel and aspirin) which was then discontinued and replaced by prasugrel monotherapy for the next 3 months of the follow-up period. During this time, one case (0.5%) of a combined ischemic and bleeding outcome was reported (39). Based on these results, plans are being made for a prospective study in which all the patients will exclusively receive prasugrel monotherapy during the study and the one-year follow-up.

    Conclusion

    Potent P2Y12 inhibitors, prasugrel or ticagrelor, are an integral part of DAPT in patients with ACS who underwent PCI and who do not have a high risk of bleeding complications. According to present studies, the protection provided by prasugrel therapy compared with ticagrelor is greater than the potential ischemic outcomes in selected groups of patients, without increased risk of bleeding, and is therefore the first treatment of choice. On the other hand, ticagrelor is the treatment of choice in patients with ACS treated with medication. In spite of the promising results of the studies involving reduced 3-month DAPT followed by continued therapy with a P2Y12 inhibitor, additional studies are required, primarily in patients with ACS, before introducing any changes to the current clinical practice.

    Literature

    1. 1.
      Capodanno D, Alfonso F, Levine GN, Valgimigli M, Angiolillo DJ. ACC/AHA Versus ESC Guidelines on Dual Antiplatelet Therapy: JACC Guideline Comparison. J Am Coll Cardiol. 2018 December 11;72 23 Pt A:2915–31.DOI
    2. 2.
      Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018 January 7;39(2):119–77.DOI
    3. 3.
      Collet JP, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021 April 7;42(14):1289–367.DOI
    4. 4.
      Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 August 16;345(7):494–502.DOI
    5. 5.
      Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 November 15;357(20):2001–15.DOI
    6. 6.
      Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 September 10;361(11):1045–57.DOI
    7. 7.
      Baldetti L, Melillo F, Moroni F, Gallone G, Pagnesi M, Venuti A, et al. Meta-Analysis Comparing P2Y12 Inhibitors in Acute Coronary Syndrome. Am J Cardiol. 2020 June 15;125(12):1815–22.DOI
    8. 8.
      Kamran H, Jneid H, Kayani WT, Virani SS, Levine GN, Nambi V, et al. Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review. JAMA. 2021 April 20;325(15):1545–55.DOI
    9. 9.
      Norgard NB, Abu-Fadel M. Comparison of prasugrel and clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Vasc Health Risk Manag. 2009;5:873–82.DOI
    10. 10.
      Wiviott SD, Antman EM, Braunwald E. Prasugrel. Circulation. 2010 July 27;122(4):394–403.DOI
    11. 11.
      Riesmeyer JS, Salazar DE, Weerakkody GJ, Ni L, Wrishko RE, Ernest CS, et al. Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy. J Clin Pharmacol. 2012 June;52(6):789–97.DOI
    12. 12.
      Erlinge D, Ten Berg J, Foley D, Angiolillo DJ, Wagner H, Brown PB, et al. Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial. J Am Coll Cardiol. 2012 November 13;60(20):2032–40.DOI
    13. 13.
      Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al. ACCOAST Investigators. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013 September 12;369(11):999–1010.DOI
    14. 14.
      Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012 October 4;367(14):1297–309.DOI
    15. 15.
      Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014 December 4;371(23):2155–66.DOI
    16. 16.
      Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014 October;34(10):1077–90.DOI
    17. 17.
      Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015 May 7;372(19):1791–800.DOI
    18. 18.
      Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, et al. ISAR-REACT 5 Trial Investigators. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2019 October 17;381(16):1524–34.DOI
    19. 19.
      Parodi G, Storey RF. Dyspnoea management in acute coronary syndrome patients treated with ticagrelor. Eur Heart J Acute Cardiovasc Care. 2015 December;4(6):555–60.DOI
    20. 20.
      Capodanno D, Angiolillo DJ. When Less Becomes More: Insights on the Pharmacodynamic Effects of Aspirin Withdrawal in Patients With Potent Platelet P2Y12 Inhibition Induced by Ticagrelor. J Am Heart Assoc. 2020 December 15;9(24):e019432.DOI
    21. 21.
      Schulz-Schüpke S, Byrne RA, Ten Berg JM, Neumann FJ, Han Y, Adriaenssens T, et al. Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J. 2015 May 21;36(20):1252–63.DOI
    22. 22.
      Capodanno D, Mehran R, Valgimigli M, Baber U, Windecker S, Vranckx P, et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol. 2018 August;15(8):480–96.DOI
    23. 23.
      Armstrong PC, Leadbeater PD, Chan MV, Kirkby NS, Jakubowski JA, Mitchell JA, et al. In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J Thromb Haemost. 2011 March;9(3):552–61.DOI
    24. 24.
      Johnson TW, Baos S, Collett L, Hutchinson JL, Nkau M, Molina M, et al. Pharmacodynamic Comparison of Ticagrelor Monotherapy Versus Ticagrelor and Aspirin in Patients After Percutaneous Coronary Intervention: The TEMPLATE (Ticagrelor Monotherapy and Platelet Reactivity) Randomized Controlled Trial. J Am Heart Assoc. 2020 December 15;9(24):e016495.DOI
    25. 25.
      Giacoppo D, Matsuda Y, Fovino LN, D’Amico G, Gargiulo G, Byrne RA, et al. Short dual antiplatelet therapy followed by P2Y12 inhibitor monotherapy vs. prolonged dual antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents: a systematic review and meta-analysis of randomized clinical trials. Eur Heart J. 2021 January 21;42(4):308–19.DOI
    26. 26.
      Galli M, Capodanno D, Andreotti F, Crea F, Angiolillo DJ. Safety and efficacy of P2Y12 inhibitor monotherapy in patients undergoing percutaneous coronary interventions. Expert Opin Drug Saf. 2021 January;20(1):9–21.DOI
    27. 27.
      Benenati S, Crimi G, Canale C, Pescetelli F, De Marzo V, Vergallo R, et al. Duration of dual antiplatelet therapy and subsequent monotherapy type in patients undergoing drug eluting stent implantation: a network Meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2020 Nov 2:pvaa127.DOI
    28. 28.
      Gargiulo G, Valgimigli M, Capodanno D, Bittl JA. State of the art: duration of dual antiplatelet therapy after percutaneous coronary intervention and coronary stent implantation - past, present and future perspectives. EuroIntervention. 2017 August 25;13(6):717–33.DOI
    29. 29.
      Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014. Eur Heart J. 2015 December 14;36(47):3320–31.DOI
    30. 30.
      Vranckx P, Valgimigli M, Jüni P, Hamm C, Steg PG, Heg D, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018 September 15;392(10151):940–9.DOI
    31. 31.
      Hahn JY, Song YB, Oh JH, Chun WJ, Park YH, Jang WJ, et al. Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial. JAMA. 2019 June 25;321(24):2428–37.DOI
    32. 32.
      Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019 June 25;321(24):2414–27.DOI
    33. 33.
      Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019 November 21;381(21):2032–42.DOI
    34. 34.
      Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, et al. Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020 June 16;323(23):2407–16.DOI
    35. 35.
      O’Donoghue ML, Murphy SA, Sabatine MS. The Safety and Efficacy of Aspirin Discontinuation on a Background of a P2Y12 Inhibitor in Patients After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis. Circulation. 2020 August 11;142(6):538–45.DOI
    36. 36.
      Baber U, Dangas G, Angiolillo DJ, Cohen DJ, Sharma SK, Nicolas J, et al. Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS. Eur Heart J. 2020 October 1;41(37):3533–45.DOI
    37. 37.
      Angiolillo DJ, Baber U, Sartori S, Briguori C, Dangas G, Cohen DJ, et al. Ticagrelor With or Without Aspirin in High-Risk Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention. J Am Coll Cardiol. 2020 May 19;75(19):2403–13.DOI
    38. 38.
      Dangas G, Baber U, Sharma S, Giustino G, Mehta S, Cohen DJ, et al. Ticagrelor With or Without Aspirin After Complex PCI. J Am Coll Cardiol. 2020 May 19;75(19):2414–24.DOI
    39. 39.
      Kogame N, Guimarães PO, Modolo R, De Martino F, Tinoco J, Ribeiro EE, et al. Aspirin-Free Prasugrel Monotherapy Following Coronary Artery Stenting in Patients With Stable CAD: The ASET Pilot Study. JACC Cardiovasc Interv. 2020 October 12;13(19):2251–62.DOI