Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Giuseppe Andò
 -- 2414 2023-04-11 11:53:07 |
2 format correct
Jessie Wu
 Meta information modification 2414 2023-04-12 02:32:16 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Alagna, G.; Mazzone, P.; Contarini, M.; Andò, G. Oral and Parenteral P2Y12 Inhibitor Antiplatelet Agents. Encyclopedia. Available online: https://encyclopedia.pub/entry/42931 (accessed on 24 December 2024).
Alagna G, Mazzone P, Contarini M, Andò G. Oral and Parenteral P2Y12 Inhibitor Antiplatelet Agents. Encyclopedia. Available at: https://encyclopedia.pub/entry/42931. Accessed December 24, 2024.
Alagna, Giulia, Paolo Mazzone, Marco Contarini, Giuseppe Andò. "Oral and Parenteral P2Y12 Inhibitor Antiplatelet Agents" Encyclopedia, https://encyclopedia.pub/entry/42931 (accessed December 24, 2024).
Alagna, G., Mazzone, P., Contarini, M., & Andò, G. (2023, April 11). Oral and Parenteral P2Y12 Inhibitor Antiplatelet Agents. In Encyclopedia. https://encyclopedia.pub/entry/42931
Alagna, Giulia, et al. "Oral and Parenteral P2Y12 Inhibitor Antiplatelet Agents." Encyclopedia. Web. 11 April, 2023.
Oral and Parenteral P2Y12 Inhibitor Antiplatelet Agents
Edit
This entry is adapted from the peer-reviewed paper 10.3390/jcdd10040163

Dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and an inhibitor of the platelet P2Y12 receptor for ADP, remains among the most investigated treatments in cardiovascular medicine. While a substantial amount of research initially stemmed from the observations of late and very late stent thrombosis events in the first-generation drug-eluting stent (DES) era, DAPT has been recently transitioning from a purely stent-related to a more systemic secondary prevention strategy. Oral and parenteral platelet P2Y12 inhibitors are currently available for clinical use. The latter have been shown to be extremely suitable in drug-naïve patients with acute coronary syndrome (ACS), mainly because oral P2Y12 inhibitors are associated with delayed efficacy in patients with STEMI and because pre-treatment with P2Y12 inhibitors is discouraged in NSTE-ACS, and in patients with recent DES implantation and in need of urgent cardiac and non-cardiac surgery. More definitive evidence is needed, however, about optimal switching strategies between parenteral and oral P2Y12 inhibitors and about newer potent subcutaneous agents that are being developed for the pre-hospital setting.

P2Y12 clopidogrel cangrelor

1. Introduction

Dual antiplatelet therapy (DAPT) consists of the combination of aspirin and an inhibitor of the platelet P2Y12 receptor for adenosine diphosphate (ADP). At the end of the 1990s, two randomized trials definitively established DAPT with aspirin and ticlopidine as the gold standard therapy after percutaneous coronary intervention (PCI) with stent implantation, in comparison to aspirin or to aspirin and anticoagulant therapy [1][2]. Ticlopidine was soon replaced by clopidogrel at the beginning of the 2000s. DAPT has proven to be among the most investigated treatments in cardiovascular medicine. Such necessity of research initially arose from the observations of late and very late stent thrombosis (ST) events occurring after first-generation drug-eluting stent (DES) implantation, highlighting lack of efficacy of clopidogrel as one of the possible drivers of thrombotic events [3] and paving the way to development of potent oral agents such as prasugrel [4] and ticagrelor [5]. More recent evidence in high-risk patients has suggested that DAPT reduces the long-term risk of cardiovascular death, spontaneous myocardial infarction (MI), stroke and major adverse cardiac events (MACE) [6][7]. After decades of research, DAPT has been moving from a stent-related to a systemic treatment among other secondary prevention strategies such as lipid-lowering therapy and control of diabetes and hypertension. Most evidence remains largely based on post-PCI patients [8], while patients that are either medically managed (e.g., those with MINOCA [9], spontaneous coronary artery dissection [10], or takotsubo syndrome [11]) or undergoing coronary artery bypass grafting (CABG) [12] remain underrepresented in clinical trials.

2. Oral P2Y12 Inhibitors

While ticlopidine was the first P2Y12 inhibitor to be associated with low-dose aspirin for DAPT, its unfavorable safety profile made it obsolete after the introduction of clopidogrel. Clopidogrel is a second-generation thienopyridine and an irreversible P2Y12 receptor antagonist that is administered as an inactive pro-drug and requires enzymatic liver conversion into its active metabolite by a series of cytochrome P450 (CYP) enzymes. After activation, clopidogrel irreversibly binds to P2Y12, an ADP receptor, on the surface of platelets, resulting in an inactivation of the glycoprotein (GP) IIb/IIIa receptor and destabilization of the platelet aggregate [6]. The recommended regimen is a loading dose of 600 mg followed by a maintenance dose of 75 mg once daily. No dose adjustment is required in CKD patients. The onset of action is particularly delayed and variable, ranging from 2 to 6 h and the offset of effect ranges from 3 to 10 days. The evidence provided by the landmark CURE trial established DAPT with clopidogrel as the standard of care after acute coronary syndrome (ACS) and after coronary stent implantation [13]. However, clopidogrel has too much inter-individual variability in platelet inhibition and has significant non responsiveness and resistance in some patients. The enzymatic liver conversion is one of the main causes of variability of clopidogrel action. CYP2C19 is one of the most important polymorphic CYP enzymes across different populations and this is associated with worse outcomes, for instance, in those with the CYP2C19*2 variant [14]. Likewise, all comedications that are inhibitors of CYP2C19 suppress clopidogrel bioactivation (e.g., some proton pump inhibitors, statins and calcium channel blockers) [15]. Moreover, poor intestinal absorption can delay the onset of action of clopidogrel, which can be worsened by concomitant administration of opioids for angina relief. Inadequate P2Y12 inhibition, especially in the setting of ACS, contributes to more frequent periprocedural complications such as need for recurrent revascularization, MI, and ST. This highlighted the need for a more potent and consistent platelet inhibition that was introduced with novel generation P2Y12 inhibitors.
Prasugrel is thienopyridine as well and an irreversible P2Y12 receptor antagonist that is administered as an inactive pro-drug and requires an enzymatic liver activation. Differently than clopidogrel, it gains a faster, greater, and more consistent degree of platelet inhibition [16]. The recommended regimen is a loading dose of 60 mg followed by a maintenance dose of 10 mg once daily, reduced to 5 mg in patients ≥75 years old or <60 kg. No dose adjustment is required in CKD patients. The onset of action is rapid, ranging from 0.5 to 4 h and the offset of effect ranges from 5 to 10 days. The TRITON-TIMI 38 trial compared prasugrel versus clopidogrel in P2Y12 inhibitor-naïve ACS patients referred to PCI [4]. Prasugrel determined a reduction in primary ischemic endpoint compared to clopidogrel, counterbalanced by a significant increase in the rate of major bleeding. Prasugrel was also compared to ticagrelor, the other potent P2Y12 inhibitor, in the recent ISAR-REACT 5 randomized trial. Prasugrel was superior in reducing the rate of death, MI, and stroke without any increase in bleeding complications [17]. Thus, prasugrel is the recommended P2Y12 inhibitor in ACS patients without high bleeding risk proceeding to PCI [18].
Ticagrelor is a direct oral reversible P2Y12 receptor inhibitor, which belongs to a novel chemical class, the cyclopentyl triazolopyrimidine. Following intestinal absorption, ticagrelor does not need to be metabolized for platelet inhibition. The recommended dose is a loading dose of 180 mg followed by a maintenance dose of 90 mg twice a day. No dose adjustment is required in CKD patients. The onset of action is rapid as well, ranging from 0.5 to 2 h and the offset of effect ranges from 3 to 4 days. The PLATO trial proved the superiority of ticagrelor compared to clopidogrel in ACS patients regarding the rate of death from vascular causes, MI, or stroke, without significant difference in major bleeding rates [5]. Nevertheless, ticagrelor also led to more patients stopping medication because of side effects, mainly dyspnea. As it is not associated with pulmonary or cardiac dysfunction, alterations in the mechanisms and the neurological pathways of the sensation of dyspnea may be involved in its pathogenesis [19].

3. Drawbacks of Oral P2Y12 Inhibitors

Despite potent P2Y12 inhibitors (prasugrel and ticagrelor) provide lower rates of ischemic events compared to clopidogrel, significant concerns remain about their onset of action. Moreover, their administration does not counterbalance the high residual platelet reactivity (HRPR) up to 4–6 h after the standard loading dose [20][21][22]. For this reason, strategies have been tested to increase the bioavailability of oral P2Y12 inhibitors, such as crushing or chewing tablets. However, pharmacokinetic and pharmacodynamic data remain limited [23][24][25]. So far, clopidogrel remains the P2Y12 inhibitor recommended in stable coronary artery disease (CAD) patients, unless specific high-risk procedural characteristics are present, such as complex left main or multivessel stenting, suboptimal stent deployment, or other conditions associated with high risk of stent thrombosis; in such cases, initial treatment with either prasugrel or ticagrelor may be considered according to European guidelines [26] if the tradeoff between risk of ischemia and bleeding is favorable [27]. All these therapies are limited by their need to be absorbed in the gastrointestinal (GI) tract before becoming available and this leads to an inevitable delay between drug intake and time of reaching effective platelet inhibition. Gastric emptying, intestinal motility, blood perfusion of the mucosa and its permeability are all factors influencing the absorption rate of medications [28]. Moreover, it has been reported that the velocity of platelet inhibition after oral intake was influenced by the clinical presentation: faster for stable CAD undergoing PCI, slower for NSTE-ACS patients, and the slowest for STEMI patients [20][29]. This phenomenon can be explained by a decreased cardiac output in ACS patients, which leads to a sympathetic system activation, and a vasoconstriction of the peripheral arteries that shunts the blood to vital organs, impairing gastric emptying, intestinal motility, and permeability of the hypo-perfused mucosa [30]. Elevated central pressure due to reduced cardiac output also leads to the release of atrial natriuretic peptide, which inhibits intestinal permeability and motility [31]. In acute settings, nausea and vomiting are common, reducing drug absorption as well. Finally, concomitant treatment with morphine, an opioid analgesic usually used to alleviate chest pain, delays gastric emptying, reduces intestinal peristalsis, and itself induces nausea and vomiting. Another barrier concerns the inability for oral administration of medications in intubated or unconscious patients. A new formulation of ticagrelor in orodispersible tablets that promptly releases its components upon contact with the oral cavity has recently become available and has been tested in a prospective trial of high-risk ACS patients. Although a superior grade of platelet inhibition was not obtained as compared with standard ticagrelor tablets, the trial confirmed the feasibility and safety of administration of ticagrelor without the need of swallowing water, that may prove to be convenient in critical ACS patients [32].
That said, following intake of oral P2Y12 inhibitors there is a variable timeframe of hours of inadequate antiplatelet protection. While the risk for ST is low with new generation stents, the delayed antiplatelet effects may still increase the risk of peri-procedural MI and impaired coronary/myocardial reperfusion, translating into worse clinical outcomes. Pre-treatment whenever possible could reduce this delay, but most recent ESC guidelines do not recommend (class III) pre-treatment with oral P2Y12 inhibitors in NSTE-ACS patients, because several trials showed no ischemic benefits and more bleeding complications [18]. In addition, treatment of stable CAD patients does not include a P2Y12 inhibitor before coronary angiography. These observations underscore the need to define strategies that can bridge the gap in platelet inhibitory effects following intake of oral P2Y12 inhibitors.

4. Parenteral P2Y12 Inhibitors

Parenteral administration of a P2Y12 inhibitor allows for immediate antiplatelet effects, skipping the delay and variability in intestinal absorption velocity and providing an enhanced platelet inhibition during the time window of inadequate response to oral agents. This is notable especially in high-risk patients undergoing PCI, who require an immediate platelet inhibition.
Cangrelor is an adenosine triphosphate-analog that is a highly specific and a direct reversible antagonist for the P2Y12 receptor on the surface of platelets. This leads to blockage of ADP-induced GP IIb/IIIa receptors and inhibition of platelet aggregation. After administration, cangrelor does not need bioactivation and is immediately ready for platelet inhibition. It is available as a lyophilized powder and it is administered initially as a 30 mcg/kg intravenous bolus prior to PCI and then continued with a 4 mcg/kg/min infusion for at least 2 h or for the duration of PCI, whichever is longer. It reaches an immediate (~2 min) onset of action and has a very short offset with a rapid (30–60 min) restoration of platelet function after its discontinuation. There is neither dosage adjustment required for renal or hepatic impairment, nor for age. It has a short plasma half-life of 3–5 min as it is rapidly inactivated via dephosphorylation by nucleotidases in the blood and the major metabolite is considered inactive. Cangrelor allows high levels of platelet inhibition (>95%) and provides further decrease in platelet aggregation in patients treated than with the more potent oral P2Y12 inhibitors [33]. This reduces the risk of periprocedural and early postprocedural complications such as MI, repeat coronary revascularization and ST. Cangrelor is the only parenteral P2Y12 receptor inhibitor that has received approval. In 2015, both the US FDA and the EMA approved it in P2Y12 naïve patients undergoing PCI, both with ACS and with CAD. A large RCT showed faster and enhanced platelet inhibition in the peri-PCI period, translating into reduced ischemic events leading to clinical approval of the drug [34]. Researchers will discuss later the CHAMPION program and more recent randomized clinical trials that have been designed to compare cangrelor vs. the more potent P2Y12 inhibitors (prasugrel and ticagrelor).
Some parenteral antithrombotic drugs that interact with multiple pathways are currently being developed for the treatment of ACS, with the aim of further reducing ischemic events without significantly increasing bleeding complications [35]. Selatogrel is a reversible binding P2Y12 inhibitor formulated for subcutaneous (SC) administration. Its molecular structure derives from incorporation of the pyrimidine group of ticagrelor into a family of compounds previously studied as P2Y12 receptor antagonists [36][37]. Preclinical studies have suggested that selatogrel is potent and selective, but also that it may have a broader therapeutic index than clopidogrel or ticagrelor with regards to increased bleeding risk while maintaining antithrombotic effect [38]. Selatogrel has a rapid onset and one study of the radiolabeled drug suggested that there were no significant plasma metabolites, and that elimination was largely fecal, predicting no significant drug–drug interactions [39]. Phase II trials in both ACS and stable, chronic CAD are now being reported with promising results. Selatogrel reliably and potently inhibits platelet reactivity within 30 min after subcutaneous administration and for approximately 8 h in patients with chronic coronary syndrome, the effect fading within 24 h [40]. In patients with AMI, a single subcutaneous injection of selatogrel rapidly induced a profound and dose-dependent inhibition of platelet activity, independently from age, sex or clinical presentation, without major bleeding events and with short-term dyspnea as the only relevant adverse event [41]. The clinical context in which selatogrel may find its place remains to be determined; however, as it provides potent, rapid and reversible P2Y12 inhibition without the need for intravenous access or infusion, it could represent a promising pre-treatment option for early prehospital administration by healthcare professionals or even from self-administration by patients during a suspected re-infarction [42]. A large-scale clinical outcomes trial (SOS-AMI, Selatogrel Outcome Study in Suspected Acute Myocardial Infarction) in patients with a recent history of AMI, employing an autoinjector for early and convenient subcutaneous self-administration of selatogrel by the patient him/herself, is now ongoing (ClinicalTrials.gov Identifier: NCT04957719).
RUC-4 (zalunfiban) is a second-generation GP IIb/IIIa inhibitor (GPI) which has shown a good safety profile and a high and limited-duration antiplatelet efficacy in both stable [43] and STEMI [44] patients. Zalunfiban is now being investigated in a large-scale Phase 3 RCT testing pre-hospital subcutaneous injection in STEMI patients (CELEBRATE, A Phase 3 Study of Zalunfiban in Subjects with ST-elevation MI, ClinicalTrials.gov Identifier: NCT04825743).

References

  1. Leon, M.B.; Baim, D.S.; Popma, J.J.; Gordon, P.C.; Cutlip, D.E.; Ho, K.K.; Giambartolomei, A.; Diver, D.J.; Lasorda, D.M.; Williams, D.O.; et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N. Engl. J. Med. 1998, 339, 1665–1671.
  2. Schömig, A.; Neumann, F.J.; Kastrati, A.; Schühlen, H.; Blasini, R.; Hadamitzky, M.; Walter, H.; Zitzmann-Roth, E.M.; Richardt, G.; Alt, E.; et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N. Engl. J. Med. 1996, 334, 1084–1089.
  3. McFadden, E.P.; Stabile, E.; Regar, E.; Cheneau, E.; Ong, A.T.; Kinnaird, T.; Suddath, W.O.; Weissman, N.J.; Torguson, R.; Kent, K.M.; et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004, 364, 1519–1521.
  4. Wiviott, S.D.; Braunwald, E.; McCabe, C.H.; Montalescot, G.; Ruzyllo, W.; Gottlieb, S.; Neumann, F.J.; Ardissino, D.; De Servi, S.; Murphy, S.A.; et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 2007, 357, 2001–2015.
  5. Wallentin, L.; Becker, R.C.; Budaj, A.; Cannon, C.P.; Emanuelsson, H.; Held, C.; Horrow, J.; Husted, S.; James, S.; Katus, H.; et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 2009, 361, 1045–1057.
  6. Bonaca, M.P.; Bhatt, D.L.; Cohen, M.; Steg, P.G.; Storey, R.F.; Jensen, E.C.; Magnani, G.; Bansilal, S.; Fish, M.P.; Im, K.; et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N. Engl. J. Med. 2015, 372, 1791–1800.
  7. Yeh, R.W.; Kereiakes, D.J.; Steg, P.G.; Windecker, S.; Rinaldi, M.J.; Gershlick, A.H.; Cutlip, D.E.; Cohen, D.J.; Tanguay, J.F.; Jacobs, A.; et al. Benefits and Risks of Extended Duration Dual Antiplatelet Therapy After PCI in Patients With and Without Acute Myocardial Infarction. J. Am. Coll. Cardiol. 2015, 65, 2211–2221.
  8. Ando, G.; De Santis, G.A.; Greco, A.; Pistelli, L.; Francaviglia, B.; Capodanno, D.; De Caterina, R.; Capranzano, P. P2Y(12) Inhibitor or Aspirin Following Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Network Meta-Analysis. JACC Cardiovasc. Interv. 2022, 15, 2239–2249.
  9. Reynolds, H.R.; Maehara, A.; Kwong, R.Y.; Sedlak, T.; Saw, J.; Smilowitz, N.R.; Mahmud, E.; Wei, J.; Marzo, K.; Matsumura, M.; et al. Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of Myocardial Infarction With Nonobstructive Coronary Arteries in Women. Circulation 2021, 143, 624–640.
  10. Waterbury, T.M.; Tarantini, G.; Vogel, B.; Mehran, R.; Gersh, B.J.; Gulati, R. Non-atherosclerotic causes of acute coronary syndromes. Nat. Rev. Cardiol. 2020, 17, 229–241.
  11. Ando, G.; Trio, O.; de Gregorio, C. Transient left ventricular dysfunction in patients with neurovascular events. Acute Card Care 2010, 12, 70–74.
  12. Tarantini, G.; Mojoli, M.; Varbella, F.; Caporale, R.; Rigattieri, S.; Ando, G.; Cirillo, P.; Pierini, S.; Santarelli, A.; Sganzerla, P.; et al. Timing of Oral P2Y(12) Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome. J. Am. Coll. Cardiol. 2020, 76, 2450–2459.
  13. Yusuf, S.; Zhao, F.; Mehta, S.R.; Chrolavicius, S.; Tognoni, G.; Fox, K.K. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 2001, 345, 494–502.
  14. Gurbel, P.A.; Tantry, U.S. Drug insight: Clopidogrel nonresponsiveness. Nat. Clin. Pract. Cardiovasc. Med. 2006, 3, 387–395.
  15. Jiang, X.L.; Samant, S.; Lesko, L.J.; Schmidt, S. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet 2015, 54, 147–166.
  16. Brandt, J.T.; Payne, C.D.; Wiviott, S.D.; Weerakkody, G.; Farid, N.A.; Small, D.S.; Jakubowski, J.A.; Naganuma, H.; Winters, K.J. A comparison of prasugrel and clopidogrel loading doses on platelet function: Magnitude of platelet inhibition is related to active metabolite formation. Am. Heart J. 2007, 153, 66.e9–66.e16.
  17. Schüpke, S.; Neumann, F.J.; Menichelli, M.; Mayer, K.; Bernlochner, I.; Wöhrle, J.; Richardt, G.; Liebetrau, C.; Witzenbichler, B.; Antoniucci, D.; et al. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N. Engl. J. Med. 2019, 381, 1524–1534.
  18. Collet, J.P.; Thiele, H.; Barbato, E.; Barthélémy, O.; Bauersachs, J.; Bhatt, D.L.; Dendale, P.; Dorobantu, M.; Edvardsen, T.; Folliguet, T.; et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur. Heart J. 2021, 42, 1289–1367.
  19. Cattaneo, M.; Faioni, E.M. Why does ticagrelor induce dyspnea? Thromb. Haemost. 2012, 108, 1031–1036.
  20. Alexopoulos, D.; Xanthopoulou, I.; Gkizas, V.; Kassimis, G.; Theodoropoulos, K.C.; Makris, G.; Koutsogiannis, N.; Damelou, A.; Tsigkas, G.; Davlouros, P.; et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ. Cardiovasc. Interv. 2012, 5, 797–804.
  21. Valgimigli, M.; Tebaldi, M.; Campo, G.; Gambetti, S.; Bristot, L.; Monti, M.; Parrinello, G.; Ferrari, R. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: The FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc. Interv. 2012, 5, 268–277.
  22. Parodi, G.; Valenti, R.; Bellandi, B.; Migliorini, A.; Marcucci, R.; Comito, V.; Carrabba, N.; Santini, A.; Gensini, G.F.; Abbate, R.; et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J. Am. Coll. Cardiol. 2013, 61, 1601–1606.
  23. Parodi, G.; Xanthopoulou, I.; Bellandi, B.; Gkizas, V.; Valenti, R.; Karanikas, S.; Migliorini, A.; Angelidis, C.; Abbate, R.; Patsilinakos, S.; et al. Ticagrelor crushed tablets administration in STEMI patients: The MOJITO study. J. Am. Coll. Cardiol. 2015, 65, 511–512.
  24. Rollini, F.; Franchi, F.; Hu, J.; Kureti, M.; Aggarwal, N.; Durairaj, A.; Park, Y.; Seawell, M.; Cox-Alomar, P.; Zenni, M.M.; et al. Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study. J. Am. Coll. Cardiol. 2016, 67, 1994–2004.
  25. Venetsanos, D.; Sederholm Lawesson, S.; Swahn, E.; Alfredsson, J. Chewed ticagrelor tablets provide faster platelet inhibition compared to integral tablets: The inhibition of platelet aggregation after administration of three different ticagrelor formulations (IPAAD-Tica) study, a randomised controlled trial. Thromb. Res. 2017, 149, 88–94.
  26. Knuuti, J.; Wijns, W.; Saraste, A.; Capodanno, D.; Barbato, E.; Funck-Brentano, C.; Prescott, E.; Storey, R.F.; Deaton, C.; Cuisset, T.; et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart J. 2020, 41, 407–477.
  27. Orme, R.C.; Parker, W.A.E.; Thomas, M.R.; Judge, H.M.; Baster, K.; Sumaya, W.; Morgan, K.P.; McMellon, H.C.; Richardson, J.D.; Grech, E.D.; et al. Study of Two Dose Regimens of Ticagrelor Compared with Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease (STEEL-PCI). Circulation 2018, 138, 1290–1300.
  28. Serenelli, M.; Pavasini, R.; Vitali, F.; Tonet, E.; Bilotta, F.; Parodi, G.; Campo, G. Efficacy and safety of alternative oral administrations of P2Y12-receptor inhibitors: Systematic review and meta-analysis. J. Thromb. Haemost. 2019, 17, 944–950.
  29. Capranzano, P.; Angiolillo, D.J. Tackling the gap in platelet inhibition with oral antiplatelet agents in high-risk patients undergoing percutaneous coronary intervention. Expert. Rev. Cardiovasc. Ther. 2021, 19, 519–535.
  30. Reilly, P.M.; Wilkins, K.B.; Fuh, K.C.; Haglund, U.; Bulkley, G.B. The mesenteric hemodynamic response to circulatory shock: An overview. Shock 2001, 15, 329–343.
  31. Wakabayashi, S.; Kitahara, H.; Nishi, T.; Sugimoto, K.; Nakayama, T.; Fujimoto, Y.; Ariyoshi, N.; Kobayashi, Y. Platelet inhibition after loading dose of prasugrel in patients with ST-elevation and non-ST-elevation acute coronary syndrome. Cardiovasc. Interv. Ther. 2018, 33, 239–246.
  32. Parodi, G.; Talanas, G.; Mura, E.; Canonico, M.E.; Siciliano, R.; Guarino, S.; Marini, A.; Dossi, F.; Franca, P.; Raccis, M.; et al. Orodispersible Ticagrelor in Acute Coronary Syndromes: The TASTER Study. J. Am. Coll. Cardiol. 2021, 78, 292–294.
  33. Schilling, U.; Dingemanse, J.; Ufer, M. Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists. Clin. Pharmacokinet. 2020, 59, 545–566.
  34. Bhatt, D.L.; Stone, G.W.; Mahaffey, K.W.; Gibson, C.M.; Steg, P.G.; Hamm, C.W.; Price, M.J.; Leonardi, S.; Gallup, D.; Bramucci, E.; et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N. Engl. J. Med. 2013, 368, 1303–1313.
  35. Zwart, B.; Parker, W.A.E.; Storey, R.F. New Antithrombotic Drugs in Acute Coronary Syndrome. J. Clin. Med. 2020, 9, 2059.
  36. Caroff, E.; Meyer, E.; Treiber, A.; Hilpert, K.; Riederer, M.A. Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y(12) antagonists for inhibition of platelet aggregation. Bioorg. Med. Chem. Lett. 2014, 24, 4323–4331.
  37. Parker, W.A.E.; Storey, R.F. Novel approaches to P2Y(12) inhibition and aspirin dosing. Platelets 2021, 32, 7–14.
  38. Rey, M.; Kramberg, M.; Hess, P.; Morrison, K.; Ernst, R.; Haag, F.; Weber, E.; Clozel, M.; Baumann, M.; Caroff, E.; et al. The reversible P2Y(12) antagonist ACT-246475 causes significantly less blood loss than ticagrelor at equivalent antithrombotic efficacy in rat. Pharmacol. Res. Perspect. 2017, 5, e00338.
  39. Ufer, M.; Huynh, C.; van Lier, J.J.; Caroff, E.; Fischer, H.; Dingemanse, J. Absorption, distribution, metabolism and excretion of the P2Y12 receptor antagonist selatogrel after subcutaneous administration in healthy subjects. Xenobiotica 2020, 50, 427–434.
  40. Storey, R.F.; Gurbel, P.A.; Ten Berg, J.; Bernaud, C.; Dangas, G.D.; Frenoux, J.M.; Gorog, D.A.; Hmissi, A.; Kunadian, V.; James, S.K.; et al. Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes. Eur. Heart J. 2020, 41, 3132–3140.
  41. Sinnaeve, P.; Fahrni, G.; Schelfaut, D.; Spirito, A.; Mueller, C.; Frenoux, J.M.; Hmissi, A.; Bernaud, C.; Ufer, M.; Moccetti, T.; et al. Subcutaneous Selatogrel Inhibits Platelet Aggregation in Patients With Acute Myocardial Infarction. J. Am. Coll. Cardiol. 2020, 75, 2588–2597.
  42. Valgimigli, M.; Landi, A. Subcutaneous RUC-4 for acute myocardial infarction: A new treatment on the horizon for pre-hospital care? EuroIntervention 2021, 17, e362–e363.
  43. Kereiakes, D.J.; Henry, T.D.; DeMaria, A.N.; Bentur, O.; Carlson, M.; Seng Yue, C.; Martin, L.H.; Midkiff, J.; Mueller, M.; Meek, T.; et al. First Human Use of RUC-4: A Nonactivating Second-Generation Small-Molecule Platelet Glycoprotein IIb/IIIa (Integrin alphaIIbbeta3) Inhibitor Designed for Subcutaneous Point-of-Care Treatment of ST-Segment-Elevation Myocardial Infarction. J. Am. Heart Assoc. 2020, 9, e016552.
  44. Bor, W.L.; Zheng, K.L.; Tavenier, A.H.; Gibson, C.M.; Granger, C.B.; Bentur, O.; Lobatto, R.; Postma, S.; Coller, B.S.; van ’t Hof, A.W.J.; et al. Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction. EuroIntervention 2021, 17, e401–e410.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Cardiac & Cardiovascular Systems
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Giulia Alagna
,
Paolo Mazzone
,
Marco Contarini
,
Giuseppe Andò
View Times: 554
Entry Collection: Hypertension and Cardiovascular Diseases
Revisions: 2 times (View History)
Update Date: 12 Apr 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback