P2Y12 Inhibitor Monotherapy and Dual Antiplatelet Therapy: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Wen-Han Feng.

Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention (PCI) with stent implantation. Although it is an effective treatment to reduce the risk of ischemic events and stent thrombosis, it increases the risk of bleeding. Newer-generations of drug-eluting stents (DES) have thinner stent struts and better design to lower the risk of stent thrombosis and have more rapid endothelialization. The role of DAPT was challenged by many clinical trials in recent years. Increasing evidence is showing P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after PCI with stent implantation in the modern era, as it could lower the risk of bleeding complications and still has enough antiplatelet effect to avoid recurrent ischemic events.

  • P2Y12 inhibitor monotherapy
  • percutaneous coronary intervention (PCI)
  • diabetes mellitus (DM)

1. Introduction

Diabetes mellitus (DM) and non-DM patients have very much different clinical characteristics. DM patients are associated with a higher risk of ischemic events and usually have more co-morbidities than non-DM patients [5,7,8][1][2][3]. In addition, DM patients usually have more complex coronary artery disease and more stents implanted during PCI than non-DM patients. Globally, the prevalence of DM has increased significantly in the past dyecadears [9][4]. Therefore, it is important to find the optimal post-PCI therapy for patients with DM. The efficacy and safety of this novel approach among patients with or without diabetes mellitus is uncertain. Although some clinical trials have shown P2Y12 inhibitor monotherapy had favorable outcomes for DM patients [10[5][6],11], they were individually underpowered. Therefore, we perform a systematic review and meta-analysis to assess the efficacy and safety of P2Y12 inhibitor monotherapy compared to DAPT in DM and non-DM patients who underwent PCI and stent implantation.

2. Current Insights

Conventionally, it is recommended that DAPT should be continued for at least 6 months (in stable coronary artery disease) or 12 months (in acute coronary syndrome) unless contraindications occur [12][7]. Early suspension of antiplatelet therapy would increase the risk of recurrent ischemic events and stent thrombosis. This concept was changed because of the advent of safer, newer-generation DES and the awareness of increased bleeding risk caused by prolonged DAPT. Based on these reasons, a new treatment strategy of using a very short period of DAPT followed by a potent P2Y12 inhibitor monotherapy was proposed. The results from this syrestematic reviewearch and meta-analysis of 29136 patients from four randomized controlled trials indicate that the P2Y12 inhibitor monotherapy could significantly lower the risk of bleeding complications without increasing the risk of ischemic events compared with standard DAPT in patients without DM. Surprisingly, P2Y12 inhibitor monotherapy significantly reduced the risk of ischemic events in patients with DM, but not the risk of bleeding complications. Currently, there is no clear biological rationale to explain this clinical finding. However, ticagrelor seemed to have better clinical effects when combined with a lower dose of aspirin in a PLATO study [13][8]. One possible hypothesis is that aspirin reduces not only the release of thromboxane A2, but also the release of prostacyclin [14][9]. The therapeutic effect of ticagrelor may be attenuated when endogenous prostacyclin production is inhibited [15,16][10][11]. It is possible that ticagrelor works better in monotherapy than in combination therapy with aspirin. Further investigations are needed to elucidate the complex interactions between these two drugs. These findings challenge contemporary practice guideline recommendations for DAPT as the standard treatment for post-PCI care. Other meta-analyses have been published on P2Y12 inhibitor monotherapy after PCI [17,18,19][12][13][14]. However, outhe researchers' meta-analysis is unique in focusing on DM patients. This distinction is important given the growing prevalence of diabetic patients and the different prognostic nature of these patients. The TWILIGHT DM substudy was the very first randomized study to show that P2Y12 inhibitor monotherapy could have better outcomes compared to standard DAPT [10][5]. However, the case number was relatively small. OuThis r studyesearch is the first meta-analysis to show a decrease in the risk of ischemic events with P2Y12 inhibitor monotherapy in patients with DM compared to standard DAPT.
One of the salient findings in the our studyresearch is that patients with DM indeed had a significantly higher risk of ischemic events after PCI in the modern era. The rate of ischemic events in DM and non-DM patients treated with standard DAPT was 18.7% vs. 12.8% in the GLOBAL LEADERS trial, 3.8% vs. 1.7% in the SMART-CHOICE trial, 5.9% vs. 2.8% in the TWILIGHT trial, and 5.1% vs. 2.7% in the TICO trial. All four clinical trials had the same findings. However, the risk of bleeding complications was only slightly higher in DM patients than in non-DM patients. There are several possible explanations for these findings. First, platelet reactivity was higher in DM patients than in non-DM patients [20][15]. Second, the turnover rate and the number of reticulated platelets were both higher in DM patients, resulting in more endothelial cell adhesion [21][16]. Third, DM patients tend to be more resistant to antiplatelet agents [22][17]. Based on these factors, the weresearchers could assume that the bleeding risk of DM patients treated with antiplatelet agents would be similar or even lower than non-DM patients. Therefore, DM patients should be treated with a different antiplatelet regimen than non-DM patients [23][18].
DM also leads to endothelial dysfunction (one of the main pathophysiologic mechanisms associated with cardiovascular disease) and is described as an independent determinant of ischemic heart disease and acute coronary syndrome [24][19]. Several biochemical pathways have been described to demonstrate the association between endothelial dysfunction and platelet activation, such as nitric oxide (NO) and prostacyclin (PGI2) [25][20]. NO, a well-known atheroprotective and vasodilating substance, may also attenuate platelet activation. Blood vessels of patients with DM have diminished NO production, enhanced NO degradation, and decreased sensitivity to NO. PGI2 is another important regulator produced by endothelial cells that inhibits platelet activation through binding to the prostacyclin receptor on platelets. DM is associated with lower levels of prostacyclin synthase in subcutaneous arteries and possibly leads to impaired formation of PGI2 [26][21]. Together, endothelial dysfunction and platelet hyperactivity make DM patients much more susceptible to cardiovascular disease than non-DM patients [27][22].
The success of P2Y12 inhibitor monotherapy was not a coincidence. Many in vitro and ex vivo investigations have shown that aspirin provided very limited additional platelet inhibition and anti-thrombotic effect to a potent P2Y12 inhibitor [28,29,30][23][24][25]. Of note, most of the patients treated with P2Y12 inhibitor monotherapy were using ticagrelor. Ticagrelor is a more potent P2Y12 inhibitor than clopidogrel and may improve endothelial function and blood viscosity [31,32][26][27]. In addition, clopidogrel is a prodrug that requires metabolism to transform into an active form. DM patients have a greater prevalence of being unresponsive to clopidogrel than non-DM patients [33][28]. Impaired drug metabolism, metabolic disorders, and competition for CYP3A4 with other drugs (e.g., statins) are possible mechanisms leading to a lower concentration of clopidogrel’s active metabolite and insufficient antiplatelet effects [34,35][29][30]. Therefore, it is possible the benefit of P2Y12 inhibitor monotherapy in patients who underwent PCI belongs to ticagrelor alone. In outhe researchers' previous real-world observational study, ticagrelor monotherapy resulted in substantially lower cardiovascular risk compared to clopidogrel monotherapy in patients with acute coronary syndrome (ACS) undergoing PCI [36][31].

3. Conclusions

Based on this resystematic reviewearch and meta-analysis, P2Y12 inhibitor monotherapy followed by a short duration of dual antiplatelet therapy could significantly decrease the risk of bleeding events without increasing the risk of stent thrombosis or myocardial infarction in the general population. The benefit of reducing bleeding events was much more significant in non-DM patients than in DM patients. Surprisingly, P2Y12 inhibitor monotherapy could lower the risk of MACCE in DM patients but not in non-DM patients. These findings support that P2Y12 inhibitor monotherapy is a feasible, alternative choice of medical treatment for patients with or without diabetes mellitus undergoing percutaneous intervention with stent implantation in the modern era.

References

  1. Kim, B.K.; Hong, S.J.; Cho, Y.H.; Yun, K.H.; Kim, Y.H.; Suh, Y.; Cho, J.Y.; Her, A.Y.; Cho, S.; Jeon, D.W.; 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, 323, 2407–2416.
  2. Yang, Y.; Park, G.M.; Han, S.; Kim, Y.G.; Suh, J.; Park, H.W.; Won, K.B.; Ann, S.H.; Kim, S.J.; Kim, D.W.; et al. Impact of diabetes mellitus in patients undergoing contemporary percutaneous coronary intervention: Results from a korean nationwide study. PLoS ONE 2018, 13, e0208746.
  3. Kedhi, E.; Généreux, P.; Palmerini, T.; McAndrew, T.C.; Parise, H.; Mehran, R.; Dangas, G.D.; Stone, G.W. Impact of coronary lesion complexity on drug-eluting stent outcomes in patients with and without diabetes mellitus: Analysis from 18 pooled randomized trials. J. Am. Coll. Cardiol. 2014, 63, 2111–2118.
  4. Lovic, D.; Piperidou, A.; Zografou, I.; Grassos, H.; Pittaras, A.; Manolis, A. The growing epidemic of diabetes mellitus. Curr. Vasc. Pharmacol. 2020, 18, 104–109.
  5. Angiolillo, D.J.; Baber, U.; Sartori, S.; Briguori, C.; Dangas, G.; Cohen, D.J.; Mehta, S.R.; Gibson, C.M.; Chandiramani, R.; Huber, K.; et al. Ticagrelor with or without aspirin in high-risk patients with diabetes mellitus undergoing percutaneous coronary intervention. J. Am. Coll. Cardiol. 2020, 75, 2403–2413.
  6. Chichareon, P.; Modolo, R.; Kogame, N.; Takahashi, K.; Chang, C.C.; Tomaniak, M.; Botelho, R.; Eeckhout, E.; Hofma, S.; Trendafilova-Lazarova, D.; et al. Association of diabetes with outcomes in patients undergoing contemporary percutaneous coronary intervention: Pre-specified subgroup analysis from the randomized global leaders study. Atherosclerosis 2020, 295, 45–53.
  7. Valgimigli, M.; Bueno, H.; Byrne, R.A.; Collet, J.P.; Costa, F.; Jeppsson, A.; Jüni, P.; Kastrati, A.; Kolh, P.; Mauri, L.; et al. 2017 esc focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with eacts. Eur. J. Cardio-Thorac. Surg. Off. J. Eur. Assoc. Cardio-Thorac. Surg. 2018, 53, 34–78.
  8. Mahaffey, K.W.; Wojdyla, D.M.; Carroll, K.; Becker, R.C.; Storey, R.F.; Angiolillo, D.J.; Held, C.; Cannon, C.P.; James, S.; Pieper, K.S.; et al. Ticagrelor compared with clopidogrel by geographic region in the platelet inhibition and patient outcomes (plato) trial. Circulation 2011, 124, 544–554.
  9. FitzGerald, G.A.; Oates, J.A.; Hawiger, J.; Maas, R.L.; Roberts, L.J., 2nd; Lawson, J.A.; Brash, A.R. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J. Clin. Investig. 1983, 71, 676–688.
  10. Cattaneo, M.; Lecchi, A. Inhibition of the platelet p2y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. J. Thromb. Haemost. JTH 2007, 5, 577–582.
  11. Warner, T.D.; Nylander, S.; Whatling, C. Anti-platelet therapy: Cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br. J. Clin. Pharmacol. 2011, 72, 619–633.
  12. Ho, A.C.; Egolum, U.; Parker, S.; Dimmel, J.; Hawkins, A.; Ling, H. P2y12 inhibitor monotherapy after a short dual antiplatelet therapy versus standard-term dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: A contemporary meta-analysis. Clin. Drug Investig. 2020, 40, 799–808.
  13. Valgimigli, M.; Gragnano, F.; Branca, M.; Franzone, A.; Baber, U.; Jang, Y.; Kimura, T.; Hahn, J.Y.; Zhao, Q.; Windecker, S.; et al. P2y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: Individual patient level meta-analysis of randomised controlled trials. BMJ (Clin. Res. Ed.) 2021, 373, n1332.
  14. Giacoppo, D.; Matsuda, Y.; Fovino, L.N.; D’Amico, G.; Gargiulo, G.; Byrne, R.A.; Capodanno, D.; Valgimigli, M.; Mehran, R.; Tarantini, G. 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, 42, 308–319.
  15. Ferreiro, J.L.; Angiolillo, D.J. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 2011, 123, 798–813.
  16. Ferroni, P.; Basili, S.; Falco, A.; Davì, G. Platelet activation in type 2 diabetes mellitus. J. Thromb. Haemost. JTH 2004, 2, 1282–1291.
  17. Angiolillo, D.J.; Bernardo, E.; Sabaté, M.; Jimenez-Quevedo, P.; Costa, M.A.; Palazuelos, J.; Hernández-Antolin, R.; Moreno, R.; Escaned, J.; Alfonso, F.; et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J. Am. Coll. Cardiol. 2007, 50, 1541–1547.
  18. Rivas Rios, J.R.; Franchi, F.; Rollini, F.; Angiolillo, D.J. Diabetes and antiplatelet therapy: From bench to bedside. Cardiovasc. Diagn. Ther. 2018, 8, 594–609.
  19. Severino, P.; D’Amato, A.; Prosperi, S.; Magnocavallo, M.; Mariani, M.V.; Netti, L.; Birtolo, L.I.; De Orchi, P.; Chimenti, C.; Maestrini, V.; et al. Potential role of enos genetic variants in ischemic heart disease susceptibility and clinical presentation. J. Cardiovasc. Dev. Dis. 2021, 8, 116.
  20. Theofilis, P.; Sagris, M.; Oikonomou, E.; Antonopoulos, A.S.; Tsioufis, K.; Tousoulis, D. Factors associated with platelet activation-recent pharmaceutical approaches. Int. J. Mol. Sci. 2022, 23, 3301.
  21. Mokhtar, S.S.; Vanhoutte, P.M.; Leung, S.W.; Yusof, M.I.; Sulaiman, W.A.W.; Saad, A.Z.M.; Suppian, R.; Rasool, A.H.G. Reduced expression of prostacyclin synthase and nitric oxide synthase in subcutaneous arteries of type 2 diabetic patients. Tohoku J. Exp. Med. 2013, 231, 217–222.
  22. Kaur, R.; Kaur, M.; Singh, J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: Molecular insights and therapeutic strategies. Cardiovasc. Diabetol. 2018, 17, 121.
  23. Armstrong, P.C.; Leadbeater, P.D.; Chan, M.V.; Kirkby, N.S.; Jakubowski, J.A.; Mitchell, J.A.; Warner, T.D. In the presence of strong p2y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J. Thromb. Haemost. JTH 2011, 9, 552–561.
  24. Baber, U.; Zafar, M.U.; Dangas, G.; Escolar, G.; Angiolillo, D.J.; Sharma, S.K.; Kini, A.S.; Sartori, S.; Joyce, L.; Vogel, B.; et al. Ticagrelor with or without aspirin after pci: The twilight platelet substudy. J. Am. Coll. Cardiol. 2020, 75, 578–586.
  25. Johnson, T.W.; Baos, S.; Collett, L.; Hutchinson, J.L.; Nkau, M.; Molina, M.; Aungraheeta, R.; Reilly-Stitt, C.; Bowles, R.; Reeves, B.C.; 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, 9, e016495.
  26. Moulias, A.; Xanthopoulou, I.; Alexopoulos, D. Does ticagrelor improve endothelial function? J. Cardiovasc. Pharmacol. Ther. 2019, 24, 11–17.
  27. Rosenson, R.S.; Chen, Q.; Najera, S.D.; Krishnan, P.; Lee, M.L.; Cho, D.J. Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: The hema-kinesis clinical trial. Cardiovasc. Diabetol. 2019, 18, 77.
  28. Angiolillo, D.J.; Fernandez-Ortiz, A.; Bernardo, E.; Ramírez, C.; Sabaté, M.; Jimenez-Quevedo, P.; Hernández, R.; Moreno, R.; Escaned, J.; Alfonso, F.; et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005, 54, 2430–2435.
  29. Angiolillo, D.J.; Jakubowski, J.A.; Ferreiro, J.L.; Tello-Montoliu, A.; Rollini, F.; Franchi, F.; Ueno, M.; Darlington, A.; Desai, B.; Moser, B.A.; et al. Impaired responsiveness to the platelet p2y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease. J. Am. Coll. Cardiol. 2014, 64, 1005–1014.
  30. Bates, E.R.; Lau, W.C.; Angiolillo, D.J. Clopidogrel-drug interactions. J. Am. Coll. Cardiol. 2011, 57, 1251–1263.
  31. Chen, P.W.; Feng, W.H.; Ho, M.Y.; Su, C.H.; Huang, S.W.; Cheng, C.W.; Yeh, H.I.; Chen, C.P.; Huang, W.C.; Fang, C.C.; et al. P2y12 inhibitor monotherapy with clopidogrel versus ticagrelor in patients with acute coronary syndrome undergoing percutaneous coronary intervention. J. Clin. Med. 2020, 9, 1657.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback