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Prüller, Florian, Lukasz Bis, Oliver Milke, Friedrich Fruhwald, Sascha Pätzold, Siegfried Altmanninger-Sock, Jolanta Siller-Matula, et al. "Cangrelor Induces More Potent Platelet Inhibition without Increasing Bleeding in Resuscitated Patients." Journal of Clinical Medicine 7, no. 11 (November 15, 2018): 442. http://dx.doi.org/10.3390/jcm7110442.
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Dual antiplatelet therapy is the standard of care for patients with myocardial infarction (MI), who have been resuscitated and treated with therapeutic hypothermia (TH). We compare the antiplatelet effect and bleeding risk of intravenous cangrelor to oral P2Y12-inhibitors in patients with MI receiving TH in a prospective comparison of two matched patient cohorts. Twenty-five patients within the CANGRELOR cohort were compared to 17 patients receiving oral P2Y12-inhibitors. CANGRELOR group (NCT03445546) and the ORAL P2Y12 Group (NCT02914795) were registered at clinicaltrials.gov. Platelet function testing was performed using light-transmittance aggregometry and monitored for 4 days. P2Y12-inhibition was stronger in CANGRELOR compared to ORAL P2Y12 (adenosine diphosphate (ADP) (area under the curve (AUC)) 26.0 (5.9–71.6) vs. 160.9 (47.1–193.7)) at day 1. This difference decreased over the following days as more patients were switched from CANGRELOR to oral P2Y12-inhibitor treatment. There was no difference in the effect of aspirin between the two groups. We did not observe significant differences with respect to thrombolysis in myocardial infarction (TIMI) or Bleeding Academic Research Consortium (BARC) classified bleedings, number of blood transfusions or drop in haemoglobin B (Hb) or hematocrit (Hct) over time. Cangrelor treatment is not only feasible and effective in resuscitated patients, but also inhibited platelet function more effectively than orally administered P2Y12-inhibitors without an increased event rate for bleeding.
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Alexopoulos, Dimitrios, Stylianos Dragasis, and Nikolaos Kafkas. "Loading with Oral P2Y12 Receptor Inhibitors: To Crush or Not to Crush?" Thrombosis and Haemostasis 119, no. 07 (May 12, 2019): 1037–47. http://dx.doi.org/10.1055/s-0039-1688790.
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AbstractOral P2Y12 receptor inhibitors represent a mainstay treatment in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. In the setting of ST-elevation myocardial infarction, when early platelet inhibition is highly desirable, the onset of action of oral P2Y12 receptor inhibitors is, however, delayed, likely due to delayed drug absorption. Crushing the tablets, which are to be used for patient loading with an oral P2Y12 receptor inhibitor, has been shown to provide earlier platelet inhibition than standard, integral tablets administration. Chewed ticagrelor tablets may also result in a similar effect. Such findings should be interpreted with caution, mainly due to the small number of patients enrolled and the nature (pharmacodynamic/pharmacokinetic) of the respective studies. Furthermore, in patients with out-of-hospital cardiac arrest, who remain comatose, crushing tablets is commonly applied in clinical practice for platelet P2Y12 receptor inhibition. In this review, we focus on current evidence regarding the role of crushed P2Y12 receptor inhibitor pills, analyzing clinical scenarios where most of the promise exists along with future expectations from this type of formulation. Large randomized studies are needed to draw firm conclusions regarding the clinical benefit of ‘crushing’ over the usual ‘not-crushing’ practice.
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Stratz, Christian, Thomas Nührenberg, Christian Valina, Nikolaus Löffelhardt, Kambis Mashayekhi, Miroslaw Ferenc, Dietmar Trenk, Franz-Josef Neumann, and Willibald Hochholzer. "Impact of Reticulated Platelets on the Antiplatelet Effect of the Intravenous P2Y12-Receptor Inhibitor Cangrelor." Thrombosis and Haemostasis 118, no. 02 (2018): 362–68. http://dx.doi.org/10.1160/th17-07-0466.
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Background Reticulated platelets are associated with impaired antiplatelet response to irreversibly acting P2Y12-receptor inhibitors. However, the impact of reticluated platelets (RP) on the reversibly acting injectable P2Y12-receptor inhibitor cangrelor is unknown. Thus, this study sought to investigate the influence of RP on cangrelor and transitioning strategies to oral P2Y12-receptor inhibitors. Methods This study randomized 110 patients undergoing elective percutaneous coronary intervention with use of cangrelor to different oral transitioning strategies loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (n = 45 each) or loading with clopidogrel 600 mg after discontinuation of cangrelor (n = 20). ADP-induced platelet reactivity was assessed by impedance aggregometry. Reticulated platelets were analysed by an automated whole blood flow cytometry and described as immature platelet count. Results There was no correlation of reticulated platelets and ADP-induced platelet reactivity in patients under treatment with cangrelor (r = 0.06, p = 0.47). This finding was consistent in all three transitioning strategies. On day 1 following treatment with cangrelor, the correlation of reticulated platelets and platelet reactivity was detectable again in patients receiving thienopyridines but not ticagrelor (all patients r = 0.37, p < 0.001; clopidogrel: r = 0.59, p = 0.01; prasugrel: r = 0.47, p < 0.001; ticagrelor r = 0.22, p = 0.13). Conclusion Platelet inhibition is not influenced by levels of reticulated platelets during infusion of cangrelor independent of oral P2Y12-receptor inhibitor transitioning strategy. These findings underline the potency of cangrelor as immediate and reversibly acting P2Y12-receptor inhibitor.
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Zhou, Xuan, Dominick J. Angiolillo, and Luis Ortega-Paz. "P2Y12 Inhibitor Monotherapy after Percutaneous Coronary Intervention." Journal of Cardiovascular Development and Disease 9, no. 10 (October 6, 2022): 340. http://dx.doi.org/10.3390/jcdd9100340.
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In patients with acute and chronic coronary artery disease undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) has been the cornerstone of pharmacotherapy for the past two decades. Although its antithrombotic benefit is well established, DAPT is associated with an increased risk of bleeding, which is independently associated with poor prognosis. The improvement of the safety profiles of drug-eluting stents has been critical in investigating and implementing shorter DAPT regimens. The introduction into clinical practice of newer generation oral P2Y12 inhibitors such as prasugrel and ticagrelor, which provide more potent and predictable platelet inhibition, has questioned the paradigm of standard DAPT durations after coronary stenting. Over the last five years, several trials have assessed the safety and efficacy of P2Y12 inhibitor monotherapy after a short course of DAPT in patients treated with PCI. Moreover, ongoing studies are testing the role of P2Y12 inhibitor monotherapy immediately after PCI in selected patients. In this review, we provide up-to-date evidence on the efficacy and safety of P2Y12 inhibitor monotherapy after a short period of DAPT compared to DAPT in patients undergoing PCI as well as outcomes associated with P2Y12 inhibitor monotherapy compared to aspirin for long-term prevention.
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Droppa, Michal, Oliver Borst, Dominik Rath, Karin Müller, Meinrad Gawaz, Deepak L. Bhatt, and Tobia Geisler. "Impact of Intravenous P2Y12-Receptor Inhibition with Cangrelor in Patients Presenting with Acute Coronary Syndrome and Cardiogenic Shock – a Case Series." Cellular Physiology and Biochemistry 42, no. 4 (2017): 1336–41. http://dx.doi.org/10.1159/000478962.
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Background/Aims: Patients with acute coronary syndromes (ACS) presenting with cardiogenic shock (CS) are at particular risk for death and adverse cardiac events. Impaired effects and absorption of oral P2Y12-receptor inhibitors due to decreased organ hypoperfusion or hypothermia and challenges regarding oral administration contribute to this risk. We report a single center experience regarding the use of intravenous P2Y12-receptor inhibitor cangrelor in patients with CS treated with percutaneous coronary intervention (PCI). Methods: Twelve patients with ACS and CS undergoing PCI, not pretreated with oral P2Y12-receptor inhibitors, were treated with cangrelor. Platelet inhibition was assessed by multiple electrode aggregometry (MEA) before and after PCI, immediately and 2 hours after stopping the cangrelor infusion. Results: Nine patients recovered from their cardiogenic shock, 3 patients died. Platelet reactivity decreased from 65.9 (SD 41.0) U before PCI to 15.8 (SD 10.8) U after PCI, 13.4 (SD 7.7) U at the end of infusion and 33.8 (SD 19.9) 2 hours after stopping the cangrelor infusion. There was no non-responder under cangrelor infusion (MEA < 46 U). Conclusions: Due to its favorable PK/PD profile, cangrelor overcomes problems with reduced absorption and effects of oral P2Y12-receptor inhibitors and should be considered for periprocedural treatment of patients with CS.
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Menozzi, Alberto, and Giorgio Caretta. "Acute coronary syndromes with high thrombotic burden: therapeutic innovations." European Heart Journal Supplements 22, Supplement_L (November 1, 2020): L97—L100. http://dx.doi.org/10.1093/eurheartj/suaa144.
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Abstract Antiplatelet agents represent one of the cornerstones of drug therapy for acute coronary syndromes (ACS). In the last decade, the arrival of prasugrel and ticagrelor, faster and more powerful oral platelet receptor P2Y12 inhibitors compared to clopidogrel, significantly improved platelet inhibition in patients with ACS. However, the reduction of thrombotic risk came at the cost of increased bleeding risk. Despite having similar indications, prasugrel and ticagrelor have different characteristics and methods of use, essentially due to a different design of the trials in which they have been studied. The optimal use of these antiplatelets in clinical practice should therefore be tailored in individual patients. In the acute phase of ACS with high thrombotic burden, all oral P2Y12 inhibitors have limitations, mainly due to the delay of onset of action related to oral administration. In this scenario, parenteral antiplatelet agents (glycoprotein inhibitors IIb/IIIa and cangrelor) may play a key role in case of percutaneous coronary interventions of high thrombotic coronary lesions and in the prevention of early thrombotic complications. Cangrelor, an intravenous inhibitor of the P2Y2 receptor, has peculiar pharmacokinetic and pharmacodynamic characteristics that make it particularly suitable to be used as an antiplatelet during coronary angioplasty as it achieves a rapid and powerful antiplatelet effect in patients not pretreated with oral medications, and has a favourable safety profile in relation to the bleeding risk.
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Jhagroe, Darshni Arishta, and Jurriën Maria ten Berg. "Managing the Antithrombotic Therapy After Percutaneous Coronary Intervention in Patients on Oral Anticoagulation." Interventional Cardiology Review 10, no. 3 (2015): 139. http://dx.doi.org/10.15420/icr.2015.10.03.139.
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In patients on chronic oral anticoagulation (OAC) who are undergoing a percutaneous coronary intervention (PCI), dual antiplatelet therapy (aspirin and a P2Y12 inhibitor) is required. However, combining dual antiplatelet therapy with OAC increases the risk of bleeding. Newer and stronger P2Y12 inhibitors also add more complexity to the regimen, as these antiplatelet agents are currently recommended as standard treatment in patients with acute coronary syndromes (ACS). It remains unclear whether these ACS patients on chronic OAC undergoing PCI should be treated with these new P2Y12 inhibitors as part of the antiplatelet therapy. Another issue to address is that new non-vitamin K oral anticoagulants have emerged as possible alternatives for stroke prevention in patients with AF. Thus, the anticoagulated patient undergoing PCI faces a treatment dilemma. Based on a real-life case, we will discuss the optimal anticoagulant and antiplatelet treatment with a review of the literature.
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Vlachou, Maria, Matthaios Didagelos, Antonios Kouparanis, Haralambos Karvounis, and Antonios Ziakas. "Bridging with Tirofiban During Temporary Withdrawal of Oral Antiplatelets for Two Major Surgical Procedures in High Ischaemic Risk Patients." Open Cardiovascular Medicine Journal 13, no. 1 (February 15, 2019): 1–4. http://dx.doi.org/10.2174/1874192401913010001.
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Background: Recent coronary stent implantation requires Dual Antiplatelet Therapy (DAPT) for at least 6 months. Serious issues are raised when non-cardiac surgery is required during this period, because of the balance between ischemic and haemorrhagic complications. Case Reports: We report 2 high ischemic risk cases requiring intermediate bleeding risk non-cardiac surgery, during the first month of DAPT initiation. Perioperative management with discontinuation of the P2Y12 inhibitor and bridging with tirofiban, while aspirin was uninterrupted, was uneventful. Conclusion: Bridging with intravenous glycoprotein IIb/IIIa receptor inhibitors may be a safe and effective alternative to P2Y12 inhibitor discontinuation in non-deferrable non-cardiac surgery.
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Chua, Su-Kiat, Lung-Ching Chen, Kou-Gi Shyu, Jun-Jack Cheng, Huei-Fong Hung, Chiung-Zuan Chiu, and Chiu-Mei Lin. "Antithrombotic Strategies in Patients with Atrial Fibrillation Following Percutaneous Coronary Intervention: A Systemic Review and Network Meta-Analysis of Randomized Controlled Trials." Journal of Clinical Medicine 9, no. 4 (April 8, 2020): 1062. http://dx.doi.org/10.3390/jcm9041062.
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Up to 10% of patients with atrial fibrillation (AF) undergo percutaneous coronary intervention (PCI). A systematic review and network meta-analysis were conducted by searching PubMed, Embase, and the Cochrane database of systematic reviews for randomized control trials that studied the safety and efficacy of different antithrombotic strategies in these patients. Six studies, including 12,158 patients were included. Compared to that in the triple antithrombotic therapy group (vitamin K antagonist (VKA) plus P2Y12 inhibitor and aspirin), thrombolysis in myocardial infarction (TIMI) major bleeding was significantly reduced in the dual antithrombotic therapy (non-vitamin K oral anticoagulants (NOACs) plus P2Y12 inhibitor) group by 47% (Odds ratio (OR), 0.53; 95% credible interval [CrI], 0.35–0.78; I2 = 0%). Besides, NOAC plus a P2Y12 inhibitor was associated with less intracranial hemorrhage compared to VKA plus single antiplatelet therapy (OR: 0.20, 95% CrI: 0.05–0.77). There was no significant difference in the trial-defined major adverse cardiac events or the individual outcomes of all-cause mortality, cardiovascular death, myocardial infarction, stroke or stent thrombosis among all antithrombotic strategies. In conclusion, antithrombotic strategy of NOACs plus P2Y12 inhibitor is safer than, and as effective as, the strategies including aspirin when used in AF patients undergoing PCI.
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Lupercio, Florentino, Shaun Giancaterino, Pedro Arturo Villablanca, Frederick Han, Kurt Hoffmayer, Gordon Ho, Farshad Raissi, et al. "P2Y12 inhibitors with oral anticoagulation for percutaneous coronary intervention with atrial fibrillation: a systematic review and meta-analysis." Heart 106, no. 8 (February 7, 2020): 575–83. http://dx.doi.org/10.1136/heartjnl-2019-315963.
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ObjectiveThis study aimed to compare the safety and efficacy of third-generation P2Y12 inhibitors versus clopidogrel in combination with oral anticoagulation (OAC) with or without aspirin in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI).MethodsWe performed a systematic review including both prospective and retrospective studies that compared dual and triple antithrombotic regimens for bleeding and major adverse cardiac events (MACE) in patients with AF undergoing PCI. We analysed rates of bleeding and MACE by P2Y12 inhibitor choice. Risk ratio (RR) 95% CIs were measured using the Mantel-Haenszel method. Where study heterogeneity was low (I2 <25%), we used the fixed effects model, otherwise the random effects model was used.ResultsA total of 22 014 patients were analysed from the seven studies included. Among patients treated with both OAC and P2Y12 inhibitor with or without aspirin, 90% (n=9708) were treated with clopidogrel, 8% (n=830) with ticagrelor, and 2% (n=191) with prasugrel. When compared with clopidogrel, use of ticagrelor (RR 1.36; 95% CI 1.18 to 1.57) and prasugrel (RR 2.11; 95% CI 1.34 to 3.30) were associated with increased rates of bleeding. Compared with clopidogrel, there were no significant differences in rates of MACE with ticagrelor (RR 1.03; 95% CI 0.65 to 1.62) or prasugrel (RR 1.49; 95% CI 0.69 to 3.24).ConclusionBased on this meta-analysis, the use of clopidogrel is associated with a lower rate of bleeding compared with ticagrelor or prasugrel in patients with AF on OAC undergoing PCI.
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Cohen, Michael V., and James M. Downey. "What Are Optimal P2Y12 Inhibitor and Schedule of Administration in Patients With Acute Coronary Syndrome?" Journal of Cardiovascular Pharmacology and Therapeutics 25, no. 2 (October 23, 2019): 121–30. http://dx.doi.org/10.1177/1074248419882923.
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Guidelines recommend treatment with a P2Y12 platelet adenosine diphosphate receptor inhibitor in patients undergoing elective or urgent percutaneous coronary intervention (PCI), but the optimal agent or timing of administration is still not clearly specified. The P2Y12 inhibitor was initially used for its platelet anti-aggregatory action to block thrombosis of the recanalized coronary artery or deployed stent. It is now recognized that these agents also offer potent cardioprotection against a reperfusion injury that occurs in the first minutes of reperfusion if platelet aggregation is blocked at the time of reperfusion. But this is difficult to achieve with oral agents which are slowly absorbed and often require time-consuming metabolic activation. Patients with ST-segment elevation myocardial infarction who usually have a large mass of myocardium at risk of infarction seldom have sufficient time for upstream-administered oral agents to achieve a therapeutic P2Y12 level of inhibition by the time of balloon inflation. However, optimal treatment could be assured by initiating an IV cangrelor infusion shortly prior to stenting followed by subsequent post-PCI transition to an oral agent, that is, ticagrelor, once success of the recanalization and absence of need for surgical intervention are confirmed. Not only should this sequence provide optimal protection against infarction, it should also negate bleeding if coronary artery bypass grafting should be required since stopping the cangrelor infusion at any time will quickly restore platelet reactivity. It is anticipated that cangrelor-induced myocardial salvage will help preserve myocardial function and significantly diminish postinfarction heart failure.
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Pereira, Naveen L., Charanjit Rihal, Ryan Lennon, Gil Marcus, Sanskriti Shrivastava, Malcolm R. Bell, Derek So, et al. "Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y12 Inhibitor Therapy." JACC: Cardiovascular Interventions 14, no. 7 (April 2021): 739–50. http://dx.doi.org/10.1016/j.jcin.2021.01.024.
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Panov, A. V. "Antithrombotic Management for Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention." Rational Pharmacotherapy in Cardiology 17, no. 4 (September 3, 2021): 628–37. http://dx.doi.org/10.20996/1819-6446-2021-07-02.
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Comprehensive protection of a patient with atrial fibrillation (AF) should not only reduce the risk of stroke and systemic embolism, but also reduce the risk coronary events and ensure high adherence to treatment. In accordance with consensus document issued by the European Heart Rhythm Association, European Society of Cardiology, European Association of Percutaneous Cardiovascular Interventions, as well as with other recent Russian Society of Cardiology Guidelines, the management of antithrombotic therapy of patients with AF undergoing percutaneous coronary intervention (PCI) requires that multiple and interconnected issues. The review article addresses questions about duration of initial triple antithrombotic therapy (TAT), selection of P2Y12 inhibitor, choice of oral anticoagulant to be combined with antiplatelet therapy, intensity of oral anticoagulation throughout combination therapy, and choice of oral anticoagulant for indefinite therapy. In general, it is recommended to refuse the routine use of TAT for most patients. Accordingly, for patients who need both anticoagulant and antiplatelet therapy, it is strongly recommended that the default strategy after recent PCI is a double antithrombotic therapy consisting of an anticoagulant and one antiplatelet, preferably from the group of P2Y12 inhibitors. When conducting combined antithrombotic therapy, preference should be given to clopidogrel compared to other, more powerful P2Y12 inhibitors and direct oral anticoagulant (DOAC) instead of vitamin K antagonists. The primary choice of DOAC in patients with AF who have undergone PCI should be carried out taking into account such factors as individual risk of stroke and bleeding, adherence to treatment, concomitant diseases, pharmacological characteristics and evidence base of a specific DOAC, taking other medications, etc. The pharmacokinetic features of rivaroxaban, which create the possibility of its single administration, the evidence base for reducing coronary risks in various variants of the course of coronary heart disease, determines the special positions of the drug for the comprehensive protection of patients with AF after PCI.
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Serebruany, Victor L., Vasily Cherepanov, Moo Hyun Kim, Oleg Litvinov, Hector A. Cabrera-Fuentes, and Thomas A. Marciniak. "Filing Sources after Oral P2Y12 Platelet Inhibitors to the Food and Drug Administration Adverse Event Reporting System (FAERS)." Cardiology 138, no. 4 (2017): 249–53. http://dx.doi.org/10.1159/000479786.
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Background: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015. Methods: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown. Results: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians. Conclusion: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor.
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Ibrahim, Khalil, Rohan Shah, Rakesh Goli, Thomas Kickler, William Clarke, Rani Hasan, Roger Blumenthal, et al. "Fentanyl Delays the Platelet Inhibition Effects of Oral Ticagrelor: Full Report of the PACIFY Randomized Clinical Trial." Thrombosis and Haemostasis 118, no. 08 (July 4, 2018): 1409–18. http://dx.doi.org/10.1055/s-0038-1666862.
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Morphine delays oral P2Y12 platelet inhibitor absorption and is associated with adverse outcomes after myocardial infarction. Consequently, many physicians and first responders are now considering fentanyl as an alternative. We conducted a single-centre trial randomizing cardiac patients undergoing coronary angiography to intravenous fentanyl or not. All participants received local anaesthetic and intravenous midazolam. Those requiring percutaneous coronary intervention (PCI) with stenting received 180 mg oral ticagrelor intra-procedurally. The primary outcome was area under the ticagrelor plasma concentration–time curve (AUC0–24 hours). The secondary outcomes were platelet function assessed at 2 hours after loading, measured by P2Y12 reaction units (PRUs) and light transmission platelet aggregometry. Troponin-I was measured post-PCI using a high-sensitivity troponin-I assay (hs-TnI). All participants completed a survey of pain and anxiety. Of the 212 randomized, 70 patients required coronary stenting and were loaded with ticagrelor. Two participants in the no-fentanyl arm crossed over to receive fentanyl for pain. In as-treated analyses, ticagrelor concentrations were higher in the no-fentanyl arm (AUC0–24 hours 70% larger, p = 0.03). Platelets were more inhibited by 2 hours in the no-fentanyl arm (71 vs. 113 by PRU, p = 0.03, and 25% vs. 41% for adenosine diphosphate response by platelet aggregation, p < 0.01). Mean hs-TnI was higher with fentanyl at 2 hours post-PCI (11.9 vs. 7.0 ng/L, p = 0.04) with a rate of enzymatic myocardial infarction of 11% for fentanyl and 0% for no-fentanyl (p = 0.08). No statistical differences in self-reported pain or anxiety were found. In conclusion, fentanyl administration can impair ticagrelor absorption and delay platelet inhibition, resulting in mild excess of myocardial damage. This newly described drug interaction should be recognized by physicians and suggests that the interaction between opioids and oral P2Y12 platelet inhibitors is a drug class effect associated with all opioids. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02683707 (NCT02683707).
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Mainka, Felipe F., Vinicius L. Ferreira, Antonio M. Mendes, Gustavo L. Marques, Fernando Fernandez-Llimos, Fernanda S. Tonin, and Roberto Pontarolo. "Safety and Efficacy of Oral Anticoagulants Therapies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Network Meta-Analysis." Journal of Cardiovascular Pharmacology and Therapeutics 25, no. 5 (June 3, 2020): 399–408. http://dx.doi.org/10.1177/1074248420930136.
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Background: Different antithrombotic treatments, from vitamin K antagonists to direct oral anticoagulants (DOACs), are available to reduce ischemic risks in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). Objective: To synthetize evidence about the benefit–risk ratio of antithrombotic treatments and their combinations in patients with AF and PCI. Methods: A network meta-analysis and a stochastic multicriteria acceptability analysis (SMAA) were performed including randomized controlled trials (RCT) that evaluate antithrombotic treatments in adults with AF and PCI. Searches were conducted in PubMed and Scopus (updated November-2019). Outcomes compared included bleeding, stroke, and death (Prospero registration: CRD42019146813). Results: Five RCTs were included (11 532 patients). Vitamin K antagonists + dual antiplatelet therapy was associated with major bleeding (odds ratio: 0.52 [95% CI: 0.32-0.86]) compared to DOAC + P2Y12. No statistical differences were found among DOAC regimens for the main outcomes, including bleeding, stroke, and death. Surface under the cumulative ranking curve analysis (SUCRA) and SMAA demonstrated edoxaban 60 mg + P2Y12 inhibitor as the worst option (28%). Apixaban 5 mg + P2Y12 inhibitor was the safest alternative (63%) in all scenarios. Conclusions: Insufficient evidence on the clinical superiority among anticoagulant regimens exists, although apixaban slightly stands out. Edoxaban was associated with more adverse events. To strength this evidence, well-designed, low risk of bias clinical trials are needed. Cost-minimization analyses are required to provide further information for clinical decision-making.
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Hochholzer, Willibald, Pascal Kleiner, Iris Younas, Christian M. Valina, Nikolaus Löffelhardt, Michael Amann, Timo Bömicke, et al. "Randomized Comparison of Oral P2Y12-Receptor Inhibitor Loading Strategies for Transitioning From Cangrelor." JACC: Cardiovascular Interventions 10, no. 2 (January 2017): 121–29. http://dx.doi.org/10.1016/j.jcin.2016.10.004.
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Sotomi, Yohei, Ken Kozuma, Kosuke Kashiwabara, Yoshiharu Higuchi, Kenji Ando, Yoshihiro Morino, Junya Ako, et al. "Randomised controlled trial to investigate optimal antithrombotic therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention: a study protocol of the OPTIMA-AF trial." BMJ Open 11, no. 12 (December 2021): e048354. http://dx.doi.org/10.1136/bmjopen-2020-048354.
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IntroductionThe optimal antithrombotic strategy for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) is uncertain. For patients with non-AF, many trials are now evaluating short 1-month dual antiplatelet therapy. In patients with AF undergoing PCI, in contrast, short dual therapy (P2Y12 inhibitor +direct oral anticoagulant (DOAC)) has not yet been evaluated.Methods and analysisThe OPTIMA-AF trial (OPTIMAl antiplatelet therapy in combination with direct oral anticoagulants in patients with non-valvular Atrial Fibrillation undergoing percutaneous coronary intervention with everolimus-eluting stent) is an investigator-initiated, open-label, nationwide, multicentre, prospective, randomised controlled trial. The primary objective is to compare the efficacy and safety of short dual therapy (1-month DOAC +P2Y12 inhibitor followed by DOAC monotherapy) against long dual therapy (12-month DOAC +P2Y12 inhibitor followed by DOAC monotherapy) in the treatment of AF subjects undergoing PCI. The primary efficacy endpoint is a composite of death or thromboembolic events (myocardial infarction, definite stent thrombosis, stroke or systemic embolism) at 365 days; and the primary safety endpoint is bleeding (International Society on Thrombosis and Haemostasis major or clinically relevant non-major bleeding) at 365 days. This trial is intended to show the non-inferiority of short dual therapy versus long dual therapy in terms of the primary efficacy endpoint and show superiority in terms of the primary safety endpoint. A total of 1090 subjects will be randomised in a 1:1 ratio at approximately 60 sites.Ethics and disseminationThis study received approval from the Certified Review Board of Osaka University (a certified research ethics committee by the Japanese Clinical Research Act). The findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberJapan Registry of Clinical Trials: jRCTs051190053; Pre-results.
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Komosa, Anna, Maciej Lesiak, Zbigniew Krasiński, Marek Grygier, Andrzej Siniawski, Włodzimierz Skorupski, Anna Olasińska-Wiśniewska, et al. "Optimal Timing of P2Y12 Inhibitor Loading in Patients Undergoing PCI: A Meta-Analysis." Thrombosis and Haemostasis 119, no. 06 (March 27, 2019): 1000–1020. http://dx.doi.org/10.1055/s-0039-1683421.
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Background and Aim The timing of P2Y12 inhibitor loading in patients undergoing percutaneous coronary intervention (PCI) is a matter of debate. The aim of our study was to compare the efficacy and safety of oral P2Y12 inhibitors: clopidogrel, ticagrelor and prasugrel administered at two different time points in relation to PCI: early (> 2 hours pre-PCI) versus late (< 2 hours pre-PCI or post-PCI). Methods This is a systematic review and meta-analysis. Randomized controlled trials and non-randomized studies were included. Outcomes evaluated were combined major adverse cardiovascular events (MACEs), myocardial infarction (MI), target vessel revascularization, death and bleeding complications. Summary estimates of the relative risks with therapy were calculated. Results Twenty-three studies met the selection criteria and included 60,907 patients. Early P2Y12 inhibitor loading was associated with a 22% relative risk reduction (RRR) of MACE (95% confidence interval [CI] = 0.68–0.89; p < 0.001). Early clopidogrel loading was associated with a 25% RRR of MACE (95% CI = 0.65–0.85; p < 0.001), a 30% RRR of MI (95% CI = 0.6–0.82; p < 0.0001) and 25% RRR of death (95% CI = 0.64–0.87; p = 0.0002), without an impact on major bleedings. In ST-elevation myocardial infarction as well as non-ST elevation acute coronary syndrome (NSTE-ACS), early clopidogrel loading resulted in 35 and 22% RRR in 30 days MACE (p < 0.001), respectively, with no impact in elective PCI. Whereas early loading with prasugrel and ticagrelor did not improve ischaemic outcomes, prasugrel administered early increased bleeding risks in NSTE-ACS. Conclusion Early clopidogrel loading is associated with a better efficacy and similar safety, whereas timing of ticagrelor or prasugrel loading had no effects on ischaemic events.
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Ratcovich, Hanna, Luigi Biasco, Frants Pedersen, Steffen Helqvist, Kari Saunamaki, Hans-Henrik Tilsted, Peter Clemmensen, et al. "Prehospital administration of P2Y12 inhibitors and early coronary reperfusion in primary PCI: an observational comparative study." Thrombosis and Haemostasis 114, no. 09 (2015): 623–31. http://dx.doi.org/10.1160/th15-01-0026.
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SummaryThe newer oral P2Y12 inhibitors prasugrel and ticagrelor have been reported to be more potent and faster-acting antiplatelet agents than clopidogrel. This study aimed to investigate whether prehospital loading with prasugrel or ticagrelor improves early coronary reperfusion as compared to prehospital loading with clopidogrel in a real-world ST-elevation myocardial infarction (STEMI) setting. Over a 70-month period, 3497 patients with on-going STEMI of less than 6 hours and without cardiac arrest or cardiogenic shock underwent primary percutaneous coronary intervention (PPCI) at our centre. The primary endpoint of this study was the proportion of patients who did not meet the criteria for TIMI (Thrombolysis In Myocardial Infarction) flow grade 3 in the infarct-related artery at initial angiography before PPCI. Pre-hospital loading with prasugrel (n = 883) or ticagrelor (n = 491) did not significantly improve coronary reperfusion as compared to prehospital loading with clopidogrel (n = 1,532) – a TIMI-flow 3 at initial angiography was absent in 71.7 %, 69.0 % and 71.5 % of patients, respectively. Major adverse cardiac event (MACE) rates were low at 30 days (3.4 % to 4.0 %) and did not significantly differ between the different P2Y12 inhibitor regimens. In conclusion, this large observational, non-randomised study is the first to show that prehospital loading with the newer P2Y12 inhibitors does not improve early coronary reperfusion as compared to prehospital loading with clopidogrel in a PPCI cohort excluding cardiac arrest and cardiogenic shock.
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Galli, Mattia, Stefano Benenati, Francesco Franchi, Fabiana Rollini, Davide Capodanno, Giuseppe Biondi-Zoccai, Giovanni Maria Vescovo, et al. "Comparative effects of guided vs. potent P2Y12 inhibitor therapy in acute coronary syndrome: a network meta-analysis of 61 898 patients from 15 randomized trials." European Heart Journal 43, no. 10 (December 16, 2021): 959–67. http://dx.doi.org/10.1093/eurheartj/ehab836.
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Abstract Aims Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. Methods and results We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65–0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96–1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. Conclusion In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. Study registration number This study is registered in PROSPERO (CRD42021258603). Key Question A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. Key Finding In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. Take Home Message A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome.
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Wang, Yanhua, Yueping Sun, Ding Li, Lin Zhang, Kemin Wang, Weiran Chai, Xinping Luo, T. Kent Gartner, and Junling Liu. "P2Y12 Is Involved in Cancer Metastasis,." Blood 118, no. 21 (November 18, 2011): 3356. http://dx.doi.org/10.1182/blood.v118.21.3356.3356.
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Abstract Abstract 3356 The platelet ADP receptor P2Y12 plays a prominent role in amplifying platelet activation, aggregation and thrombus formation, and the P2Y12 inhibitor Clopidogrel is widely used clinically to treat coronary artery, peripheral vascular and cerebrovascular diseases. Recently, several publications analyzed the TRITON-TIMI 38 clinical trial (test the efficacy and safety of Prasugrel, a newly FDA approved thienopyridine P2Y12 inhibitor) revealing an increase in multiple types of solid tumors with Prasugrel use, casting doubt on the safety of anti-platelet therapy targeting P2Y12. In this study, we used animal models to investigate the safety of targeting P2Y12, and to elucidate the probable mechanism for the effects of P2Y12 antagonists on metastasis. Tumor growth and metastasis are basic features of malignant cancer. Pulmonary metastasis in the experimental, and spontaneous mouse metastasis models were used to identify the role of P2Y12, and the effects of its inhibitors in tumor growth and metastasis. In the experimental pulmonary metastasis group, one week before tail vein injection of 2×105 melanoma B16 cells, wild type (WT) and P2y12–/– mice were treated every other day with PBS, Clopidogrel or Prasugrel by oral gavage and continue in whole experiment process. Tumor nodules were counted, and the average nodule sizes measured at 20 days after B16 cell injection. P2y12–/– mice had fewer lung metastatic loci than the lungs of the WT controls. The experimental and control lungs had similar size nodules. But Clopidogrel dose dependently (1.5mg/kg and 30mg/kg) caused an increase of metastatic loci and loci size in both WT and P2y12–/– mice. Prasugrel (0.2mg/kg and 4mg/kg) did not affect the number or size of metastatic loci produced in either strain. These results demonstrated that p2y12 deficiency negatively affected cancer metastasis.In contrast, Clopidogrel, but not Prasugrel, promotes metastasis and cancer growth. Importantly, Clopidogrel induced metastasis promotion and growth was not P2Y12 dependent. A plausible explanation of this difference between the two drugs may reside in the fact that both are pro-drugs of thienopyridine family. Presumably, activation of the pro-drug clopidogrel, but not Prasugrel produces one or more metabolites able to promote cancer growth and metastasis in vivo. This supposition was tested, in part by asking if the effects of Clopidogrel are limited to the B16 model of metastasis. The Lewis lung carcinoma (LLC) spontaneous pulmonary metastasis model was used for this purpose. LLC cells (2.0×106) were implanted intradermally in each mouse. Surgery was done 14 days after cell implantation to completely remove the primary tumors (about 1.0g or 1cm3 in size). One month later, lungs were removed, rinsed with PBS, and pulmonary metastatic nodules counted and measured. P2Y12 deficiency decreased the spontaneous formation of pulmonary metastatic loci, but had no effect on the primary tumor. Also, Clopidogrel, dose dependently promoted lung metastasis. Next, the mechanism of the effect of P2Y12 absence on tumor metastasis was investigated. In vitro aggregation experiments revealed that B16 melanoma cells directly interact with p2y12+/+ platelets and cause platelet-cancer cell aggregation. In contrast, P2Y12 deficiency results in significantly less or no cancer cell-platelet aggregation. Interestingly, LLC cells do not cause platelet aggregation. Immunohistochemistry and immunofluorescence analyses of lung samples from the spontaneous metastasis model indicated an obvious attenuation of recruitment of VEGFR1+ bone marrow derived cell clusters, and extracellular matrix fibronectin deposition in lungs, which presumably are required for metastatic niche formation. Moreover, this effect is transplantable, as wild-type mice reconstituted with p2y12–/– bone marrow have a similar phenotype as P2y12–/– mice. These results imply that the mechanism of P2Y12 function on cancer metastasis is complicated, probably mediated through regulation of both cancer cell-platelet direct interaction and metastatic niche formation. Further work is needed to resolve this issue. In summary, it is clear that P2Y12 is a safe drug target for anti-thrombotic therapy. But, metabolic derivatives of the pro-drug Clopidogrel apparently promote cancer metastasis and growth; whereas the newly approved pro-drug Prasugrel lacks that effect in animal models, and hopefully in humans. Disclosures: No relevant conflicts of interest to declare.
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Farooq, Muhammad Zain, Prasanth Lingamaneni, Muhammad Saad Farooq, Aakash Putta, Sheeba Ba Aqeel, VV Pavan Kedar Mukthinuthalapati, Ankit Mangla, and Paul Rubinstein. "Comparison of New Oral Anticoagulants (NOAC) Based Double Therapy Versus Vitamin K Antagonist Based Triple Therapy in Patients Undergoing Percutaneous Coronary Intervention with Atrial Fibrillation: A Systematic Review and Meta-Analysis." Blood 134, Supplement_1 (November 13, 2019): 4963. http://dx.doi.org/10.1182/blood-2019-129607.
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Introduction: Current expert recommendations recommend double therapy (DT) over triple therapy (TT) in atrial fibrillation patients post percutaneous coronary intervention (PCI) to prevent the incidence of stroke. Though previous studies have focused on DT (oral anticoagulant [OAC] + P2Y12 inhibitor (including clopidogrel, ticagrelor and prasugrel)) versus TT (OAC + P2Y12 inhibitor and aspirin) strategy, no study assessed which OAC was more effective in the prevention of cardiovascular events and stroke. To this end we performed a systematic review and meta-analysis to assess whether non-vitamin K oral anticoagulants (NOAC) based DT strategy is comparable with vitamin K antagonist-based TT in patients with AF after PCI. Methods: Embase, Ovid, Pubmed and Scopus were extensively searched for only phase 2 and 3 clinical trials comparing NOAC based DT with VKA based TT from inception of these databases till June 2019 by two independent reviewers. The endpoints were all-cause mortality, Thrombolysis in Myocardial Infarction (TIMI) major bleeding, cardiovascular mortality and myocardial infarction. Cochrane Collaboration's tool was used for risk of bias assessment. Statistical heterogeneity was quantified using I2 statistics. Publication bias was assessed with Eggers regression test. Estimates were reported as hazard ratios (HR) with 95% confidence intervals (CI) using random effect model. Rivaroxaban 15 mg once daily dose from PIONEER-AF was included. From REDUAL-PCI trial we included dabigatran 110 mg BID and 150 mg BID doses. AUGUSTUS trial used 5 mg BID or 2.5 mg BID dosing of apixaban. Results: 402 trials were retrieved in the initial search which were analyzed according to PRISMA (Preferred Reporting Items for Systematic review and Meta-Analyses) guidelines. Three trials (Augustus, PIONEER AF-PCI and RE-DUAL PCI) were extracted that met the inclusion criteria and included in the final analysis evaluating 8754 patients. Twenty seven percent were females. Mean age was 71 years. PCI was done for acute coronary syndrome in 44% of the patients. Mean calculated CHA2DS2-VASc was 4 which qualifies the use of oral anticoagulants. Only PIONEER AF-PCI and RE-DUAL PCI trials described the type of stent used for PCI. Drug eluting stents were used in 71% of the patients. There was no evidence of publication bias in our analysis (P=.78). The studies overall had low risk of bias. Our analysis showed no statistically significant difference in usage of NOAC + P2Y12 inhibitor compared to triple therapy consisting vitamin K antagonist in regards to all-cause mortality, (HR 0.92, 95% CI 0.72-1.18, P=.52), thrombolysis in myocardial infarction (TIMI) major bleeding (HR 0.91, 95% CI 0.38-2.16, P=.83), cardiovascular mortality (HR 0.95, 95% CI 0.71-1.28, P=.75), stroke (HR 1.07, 95% CI 0.67-1.71, P=.78),stent thrombosis (HR 0.72, 95% CI 0.42-1.23, P=0.23) and myocardial infarction (HR 0.88, 95% CI 0.68-1.13, P=.32). Conclusion: We conclude that there is no difference between the usage of NOAC including rivaroxaban, dabigatran and apixaban in dual regimen vs triple therapy with VKA (warfarin). However, some limitations need to be considered such as heterogeneity across patients in terms of indication for PCI (elective vs emergency), choice of P2Y12 inhibitor (clopidogrel vs ticagrelor vs prasugrel), mean duration of therapy (range 6-12 months) and mean length of follow-up (range 6-14 months). In future clinical practice, post-PCI antithrombotic regimens in AF will likely consist of a single P2Y12 inhibitor plus NOAC. Disclosures No relevant conflicts of interest to declare.
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Katz, Moshe, Ehud Regev, Avi Sabbag, Israel Mazin, Arsalan Abu-Much, Andrew Kukuy, Anna Mazo, et al. "Chewing versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in Acute Coronary Syndrome - the CHEERS study." Thrombosis and Haemostasis 117, no. 04 (2017): 727–33. http://dx.doi.org/10.1160/th16-09-0728.
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SummaryIt was the study objective to evaluate whether chewing a 180 mg loading dose of ticagrelor versus an equal dose of traditional oral administration, enhances inhibition of platelet aggregation 1 hour (h) after administering a ticagrelor loading dose in non-ST elevation myocardial infarction (NSTEMI) patients. Dual anti-platelet therapy represents standard care for treating NSTEMI patients. Ticagrelor is a direct acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Fifty NSTEMI patients were randomised to receive either a chewing loading dose of 180 mg ticagrelor or an equal standard oral dose of ticagrelor. Platelet reactivity was evaluated by VerifyNow at baseline, 1 and 4 h post-loading dose. Results are reported in P2Y12 reaction units. Patients then continued to receive standard 90 mg oral ticagrelor twice daily. Baseline characteristics did not differ between the two groups. P2Y12 reaction units in the chewing group compared with the standard group at 0, 1 and 4 h after ticagrelor loading dose were: 245 vs 239 (p=0.59), 45 vs 130 (p=0.001) and 39 vs 60 (p=0.12), respectively, corresponding to a relative inhibition of platelet aggregation of 83 % vs only 47 % at 1 h (p< 0.001), and 84 % vs 77 % (p=0.59) at 4 h. Major adverse cardiac and cardiovascular events at 30 days were low (2 %), occurring in only one patient in the standard group. In conclusion, chewing a 180 mg ticagrelor loading dose is feasible and facilitates both faster and improved early inhibition of platelet aggregation in NSTEMI patients, compared with a standard oral-loading dose.Supplementary Material to this article is available online at www.thrombosis-online.com.
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Erlich, A. D. "Possibility of using dabigatran in patients with atrial fibrillation and acute coronary syndrome and PCI." Medical Council, no. 5 (April 4, 2019): 30–35. http://dx.doi.org/10.21518/2079-701x-2019-5-30-35.
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This article is devoted to the problem of combined antithrombotic therapy in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) due to acute coronary syndrome (ACS). Traditionally, these patients require an oral anticoagulant (OAC) to prevent stroke and dual anti-platelet therapy (DAT) to prevent coronary complications. The necessity of combining various antithrombotic drugs, since this greatly increases the risk of bleeding is becoming an increasing relevant clinical problem. The prolonged triple therapy in the form of a combination of OAC and DAT does not bring additional benefit to the patients, but, on the contrary, may be potentially dangerous. Currently, the possibility of using several new oral anticoagulants (NOAC) in patients with AF and ACS/PCI in the form of dual therapy has been proven: combination of OAC and p2Y12 inhibitor. The article focuses on the RE-DUAL PCI study, in which the use of dabigatran at both doses permitted in AF (150 mg twice daily and 110 mg twice daily) in combination with the p2Y12 inhibitor was associated with fewer bleeding complications than during the triple therapy in the form of OAK + DAT.The article presents a clinical case of the possibility of management of a patient with AF and ACS under the modern clinical guidelines, as well as an overview of current guidelines for the use of OAC and DAT in patients with AF undergoing PCI.
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Sukhinina, T. S., D. V. Pevzner, A. V. Mazurov, T. N. Vlasik, N. G. Solovieva, N. S. Kostritca, R. M. Shakhnovich, and I. S. Yavelov. "The role of platelet glycoprotein IIb / IIIa inhibitors in current treatment of acute coronary syndrome." Kardiologiia 62, no. 4 (April 30, 2022): 64–72. http://dx.doi.org/10.18087/cardio.2022.4.n2020.
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Current management of patients with acute coronary syndrome (ACS) includes a dual antiplatelet therapy with acetylsalicylic acid and a platelet P2Y12 receptor inhibitor. For patients without a high risk of bleeding, prasugrel and ticagrelor are preferred, since their effect is more pronounced, less dependent on metabolism of a specific patient, and occurs faster that the effect of clopidogrel. The prescription rate of platelet glycoprotein IIb/IIIa (GP IIb / IIIa) receptor inhibitors has considerably decreased. However, these drugs remain relevant in percutaneous coronary interventions in patients with a high risk of coronary thrombosis or a massive coronary thrombus, in thrombotic complications of the procedure, and in the “no-reflow” phenomenon. The intravenous route of GP IIb / IIIa inhibitor administration provides their effectiveness in patients with difficulties of drug intake or with impaired absorption of oral medications. This review presents clinical and pharmacological characteristics of various GP IIb / IIIa inhibitors and data of randomized clinical studies and registries of recent years that evaluated results of their use in patients with ACS.
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Brand, Aarent RT, Eline Houben, Irene D. Bezemer, Frank L. J. Visseren, Michiel L. Bots, Ron MC Herings, and Gert-Jan de Borst. "Platelet aggregation inhibitor prescription for newly diagnosed peripheral arterial disease in the Netherlands: a cohort study." BMJ Open 11, no. 1 (January 2021): e041715. http://dx.doi.org/10.1136/bmjopen-2020-041715.
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ObjectivesPharmacological treatment of peripheral arterial disease (PAD) comprises of antiplatelet therapy (APT), blood pressure control and cholesterol optimisation. Guidelines provide class-I recommendations on the prescription, but there are little data on the actual prescription practices. Our study provides insight into the prescription of medication among patients with PAD in the Netherlands and reports a ‘real-world’ patient journey through primary and secondary care.DesignWe conducted a cohort study among patients newly diagnosed with PAD between 2010 and 2014.SettingData were obtained from the PHARMO Database Network, a population-based network of electronic pharmacy, primary and secondary healthcare setting records in the Netherlands. The source population for this study comprised almost 1 million individuals.Participants‘Newly diagnosed’ was defined as a recorded International Classification of Primary Care code for PAD, a PAD-specific WCIA examination code or a diagnosis recorded as free text episode in the general practitioner records with no previous PAD diagnosis record and no prescription of P2Y12 inhibitors or aspirin the preceding year. The patient journey was defined by at least 1 year of database history and follow-up relative to the index date.ResultsBetween 2010 and 2014, we identified 3677 newly diagnosed patients with PAD. Most patients (91%) were diagnosed in primary care. Almost half of all patients (49%) had no APT dispensing record. Within this group, 33% received other anticoagulant therapy (vitamin K antagonist or direct oral anticoagulant). Mono-APT was dispensed as aspirin (40% of patients) or P2Y12 inhibitors (2.5% of patients). Dual APT combining aspirin with a P2Y12 inhibitor was dispensed to 8.5% of the study population.ConclusionHalf of all patients with newly diagnosed PAD are not treated conforming to (international) guideline recommendations on thromboembolism prevention through APT. At least 33% of all patients with newly diagnosed PAD do not receive any antithrombotic therapy. Evaluation and improvement of APT prescription and thereby improved prevention of (secondary) cardiovascular events is warranted.
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Rashid, Khalid, Muhammad Aamir Waheed, Hafeez Ur Rehman, and Abdel-Naser Elzouki. "Severe diarrhoea due to use of P2Y12 inhibitor ticagrelor: a rarely reported adverse event." BMJ Case Reports 14, no. 7 (July 2021): e242199. http://dx.doi.org/10.1136/bcr-2021-242199.
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Ticagrelor is a part of dual antiplatelet therapy (DAPT) which has proven benefits in patients with acute coronary syndrome especially in those undergoing percutaneous coronary intervention (PCI). However, like most other drugs, it can lead to undesired and adverse effects such as dyspnoea, easy bruising and gastrointestinal bleeding. We present a case of 70-year-old woman who developed diarrhoea following initiation of DAPT comprising of aspirin and ticagrelor following PCI. After excluding more common causes, it was attributed to ticagrelor administration and completely resolved after it was replaced with another oral antiplatelet agent. On follow-up, the patient reported complete resolution of symptoms.
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Mori, Hiroyoshi, Takuya Mizukami, Atsuo Maeda, Kazuki Fukui, Yoshihiro Akashi, Junya Ako, Yuji Ikari, et al. "A Japanese Dose of Prasugrel versus a Standard Dose of Clopidogrel in Patients with Acute Myocardial Infarction from the K-ACTIVE Registry." Journal of Clinical Medicine 11, no. 7 (April 4, 2022): 2016. http://dx.doi.org/10.3390/jcm11072016.
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Background: Dual antiplatelet therapy (DAPT) with aspirin plus P2Y12 inhibitor is used as a standard therapy for patients with acute myocardial infarction (AMI) treated with drug-eluting stents (DESs). In Japan, clopidogrel was the major P2Y12 inhibitor used for a decade until the new P2Y12 inhibitor, prasugrel, was introduced. Based on clinical studies considering Japanese features, the set dose for prasugrel was reduced to 20 mg as a loading dose (LD) and 3.75 mg as a maintenance dose (MD); these values are 60 and 10 mg, respectively, globally. Despite this dose discrepancy, little real-world clinical data regarding its efficacy and safety exist. Methods: From the K-ACTIVE registry, based on the DAPT regimen, patients were divided into a prasugrel group and a clopidogrel group. The ischemic event was a composite of cardiovascular death, non-fatal MI, and non-fatal stroke. The bleeding event was type 3 or 5 bleeding based on the Bleeding Academic Research Consortium (BARC) criteria. Results: Substantially more patients were prescribed prasugrel (n = 2786) than clopidogrel (n = 890). Clopidogrel tended to be selected over prasugrel in older patients with numerous comorbidities. Before adjustments were made, the cumulative incidence of ischemic events at 1 year was significantly greater in the clopidogrel group than in the prasugrel group (p = 0.007), while the cumulative incidence of bleeding events at 1 year was comparable between the groups (p = 0.131). After adjustments were made for the age, sex, body weight, creatine level, type of AMI, history of MI, approach site, oral anticoagulation therapy, presence of multivessel disease, Killip classification, and presence of intra-aortic balloon pumping, both ischemic and bleeding events became comparable between the groups. Conclusion: A Japanese dose of prasugrel was commonly used in AMI patients in the real-world database. Both the prasugrel and clopidogrel groups showed comparable rates of 1 year ischemic and bleeding events.
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Bor, Wilbert, and Diana A. Gorog. "Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome." Journal of Clinical Medicine 9, no. 7 (June 27, 2020): 2020. http://dx.doi.org/10.3390/jcm9072020.
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Acute coronary syndrome and atrial fibrillation are both common and can occur in the same patient. Combination therapy with dual antiplatelet therapy and oral anticoagulation increases risk of bleeding. Where the two conditions coexist, careful consideration is needed to determine the optimal antithrombotic treatment to reduce the risks of future ischaemic events associated with both conditions. Choices can be made in intraprocedural anticoagulation, type and dosing of oral anticoagulant, duration of combination therapy, and selection of P2Y12 inhibitor including genetic testing. This review article provides an overview of the available evidence to support clinicians in finding the delicate balance between antithrombotic efficacy and bleeding risk in patients with acute coronary syndrome and atrial fibrillation.
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Alexopoulos, Dimitrios, Christos Pappas, Danai Sfantou, and John Lekakis. "Cangrelor in Percutaneous Coronary Intervention: Current Status and Perspectives." Journal of Cardiovascular Pharmacology and Therapeutics 23, no. 1 (June 15, 2017): 13–22. http://dx.doi.org/10.1177/1074248417715004.
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Cangrelor is an intravenously administered P2Y12 receptor antagonist with very fast, potent, and quickly reversible action. In the CHAMPION PHOENIX trial, cangrelor provided an improved anti-ischemic protection compared with clopidogrel, without increasing the risk of severe bleeding. Cangrelor is currently approved by drug regulating authorities for patients undergoing percutaneous coronary intervention (PCI) without prior treatment with a P2Y12 receptor antagonist and not receiving a glycoprotein IIb/IIIa inhibitor, while its use is endorsed with a class IIb recommendation by the European Society of Cardiology guidelines. Several subanalyses of CHAMPION PHOENIX trial have tried to elucidate the role of cangrelor in PCI, including its usefulness during a 2-hour landmark analysis, impact on intraprocedural stent thrombosis, and reduction in myocardial infarction (MI) rate. The influence of gender, geographic region, access site, and bivalirudin use on cangrelor’s effects has also been reported. In patients with ST elevation MI and in clinical scenarios of disturbed absorption of oral antiplatelet agents or in need of an intravenous agent, cangrelor may surpass oral agents’ drawbacks. Transitioning to an oral agent is mandatory following cangrelor infusion discontinuation, although ticagrelor may be administered earlier without any pharmacodynamic interaction. Nevertheless, the clinical role of cangrelor in conjunction with administration of prasugrel or ticagrelor remains unclear. Accruing real-life experience is expected to improve our understanding of cangrelor’s role in everyday clinical practice.
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Abraham, Neena S., Alan N. Barkun, Bryan G. Sauer, James Douketis, Loren Laine, Peter A. Noseworthy, Jennifer J. Telford, and Grigorios I. Leontiadis. "American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period." Journal of the Canadian Association of Gastroenterology 5, no. 2 (March 17, 2022): 100–101. http://dx.doi.org/10.1093/jcag/gwac010.
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Abstract We conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1–7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y12 receptor inhibitor for patients on a single P2Y12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1–7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y12 receptor inhibitor drugs because of insufficient evidence.
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Carrillo-Aleman, Luna, Francisco Marín, José M. Rivera-Caravaca, Nuria Vicente-Ibarra, Elena Candela-Sanchez, Maria A. Esteve-Pastor, Teresa Lozano, et al. "Switching of Oral P2Y12 Inhibitor Treatment in Patients with Acute Coronary Syndrome: Prevalence, Predictors, and Prognosis." Clinical Drug Investigation 39, no. 3 (January 8, 2019): 275–83. http://dx.doi.org/10.1007/s40261-018-0736-z.
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Tarantini, Giuseppe, Marco Mojoli, Ferdinando Varbella, Roberto Caporale, Stefano Rigattieri, Giuseppe Andò, Plinio Cirillo, et al. "Timing of Oral P2Y12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome." Journal of the American College of Cardiology 76, no. 21 (November 2020): 2450–59. http://dx.doi.org/10.1016/j.jacc.2020.08.053.
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Verlinden, Nathan J., James C. Coons, Carlo J. Iasella, and Sandra L. Kane-Gill. "Triple Antithrombotic Therapy With Aspirin, P2Y12 Inhibitor, and Warfarin After Percutaneous Coronary Intervention." Journal of Cardiovascular Pharmacology and Therapeutics 22, no. 6 (March 9, 2017): 546–51. http://dx.doi.org/10.1177/1074248417698042.
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Background: Triple antithrombotic therapy is used in patients who require systemic anticoagulation and undergo percutaneous coronary intervention (PCI) requiring dual antiplatelet therapy. Bleeding with this combination is significant; however, few studies have described outcomes with the use of newer oral P2Y12 inhibitors in this setting. Objectives: We aimed to compare outcomes among patients prescribed triple therapy with prasugrel or ticagrelor compared to triple therapy with clopidogrel in patients who underwent PCI and required warfarin. Methods: We retrospectively evaluated 168 patients who received either prasugrel (n = 32) or ticagrelor (n = 10) and were matched (1:3) to those who received clopidogrel (n = 126) at the time of discharge from the index PCI visit. Matching was performed based on age ±10 years, sex, and indication for PCI. The primary outcome was the incidence of any bleeding during the 12-month follow-up. We also evaluated major adverse cardiovascular and cerebrovascular events (MACCEs). Results: Patient baseline characteristics were similar between groups. There was a significant excess of bleeding in patients who received prasugrel or ticagrelor compared to clopidogrel as part of triple therapy (28.6% vs 12.7%; odds ratio, 3.3; 95% confidence interval, 1.38-8.34). No differences were seen between groups in MACCEs. Conclusions: The use of prasugrel or ticagrelor as part of triple antithrombotic therapy among patients who underwent PCI and received warfarin was associated with significantly more bleeding compared to patients who received clopidogrel. Therefore, higher potency P2Y12 inhibitors should be used cautiously in these patients.
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Eindhoven, Daniëlle C., Alexander D. Hilt, Thomas C. Zwaan, Martin J. Schalij, and C. Jan Willem Borleffs. "Age and gender differences in medical adherence after myocardial infarction: Women do not receive optimal treatment – The Netherlands claims database." European Journal of Preventive Cardiology 25, no. 2 (November 22, 2017): 181–89. http://dx.doi.org/10.1177/2047487317744363.
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Background Following myocardial infarction, medication is, besides lifestyle interventions, the cornerstone treatment to improve survival and minimize the occurrence of new cardiovascular events. Still, data on nationwide medication adherence are scarce. This study assesses medical adherence during one year following myocardial infarction, stratifying per type of infarct, age and gender. Design Retrospective cohort study. Methods In The Netherlands, all inhabitants are by law obliged to have health insurance and all claims data are centrally registered. In 2012 and 2013, all national diagnosis-codings of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) were acquired. Furthermore, information on retrieved medication was extracted from the Dutch Pharmacy Information System. Twelve months after discharge, the retrieved medication at the pharmacy of each pharmacological therapy (aspirin-species, P2Y12-inhibitor, statin, beta-blocker, angiotensin-converting enzyme-/angiotensin 2-inhibitor, vitamin-K antagonists or novel oral anticoagulant) were analysed. Results In total, 59,534 patients (67 ± 13 years, 39,545 (66%) male, 57% NSTEMI) were included, of whom 52,672 (88%) patients were analysed for one-year medical adherence. STEMI patients more often achieved optimal medical adherence than NSTEMI patients (60% vs. 40%, p ≤ 0.001). In both STEMI and NSTEMI, use of all five indicated drugs was higher in male patients compared with female (STEMI male 61% vs. female 57%, p ≤ 0.001; NSTEMI male 43% vs. female 37%, p ≤ 0.001. With increasing age, a gradual decrease was observed in the use of aspirin, P2Y12-inhibitors and statins. Conclusion Age and gender differences existed in medical adherence after myocardial infarction. Medical adherence was lower in women, young patients and elderly patients, specifically in NSTEMI patients.
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Chen, Keyong. "Novel Oral P2Y12 Inhibitor Prasugrel vs. Clopidogrel in Patients with Acute Coronary Syndrome: Evidence Based on 6 Studies." Medical Science Monitor 21 (2015): 1131–37. http://dx.doi.org/10.12659/msm.893914.
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Saad, Marwan, Jared Tobolski, Dhaval Kolte, Yongfei Wang, Karl Minges, Ravi S. Hira, Jeptha P. Curtis, and Jinnette Dawn Abbott. "Duration of P2Y12 inhibitor Prescription After Percutaneous Coronary Intervention in Patients on Oral Anticoagulants (from NCDR CathPCI Registry)." American Journal of Cardiology 133 (October 2020): 182–84. http://dx.doi.org/10.1016/j.amjcard.2020.07.029.
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van der Sangen, Niels M. R., Ho Yee Cheung, Niels J. W. Verouden, Yolande Appelman, Marcel A. M. Beijk, Bimmer E. P. M. Claessen, Ronak Delewi, et al. "Cangrelor Use in Routine Practice: A Two-Center Experience." Journal of Clinical Medicine 10, no. 13 (June 26, 2021): 2829. http://dx.doi.org/10.3390/jcm10132829.
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Cangrelor is the first and only intravenous P2Y12-inhibitor and is indicated when (timely) administration of an oral P2Y12 inhibitor is not feasible in patients undergoing percutaneous coronary intervention (PCI). Our study evaluated the first years of cangrelor use in two Dutch tertiary care centers. Cangrelor-treated patients were identified using a data-mining algorithm. The cumulative incidences of all-cause death, myocardial infarction, definite stent thrombosis and major bleeding at 48 h and 30 days were assessed using Kaplan–Meier estimates. Predictors of 30-day mortality were identified using uni- and multivariable Cox regression models. Between March 2015 and April 2021, 146 patients (median age 63.7 years, 75.3% men) were treated with cangrelor. Cangrelor was primarily used in ST-segment elevation myocardial infarction (STEMI) patients (84.2%). Approximately half required cardiopulmonary resuscitation (54.8%) or mechanical ventilation (48.6%). The cumulative incidence of all-cause death was 11.0% and 25.3% at 48 h and 30 days, respectively. Two cases (1.7%) of definite stent thrombosis, both resulting in myocardial infarction, occurred within 30 days, but after 48 h. No other cases of recurrent myocardial infarction transpired within 30 days. Major bleeding occurred in 5.6% and 12.5% of patients within 48 h and 30 days, respectively. Cardiac arrest at presentation was an independent predictor of 30-day mortality (adjusted hazard ratio 5.20, 95%-CI: 2.10–12.9, p < 0.01). Conclusively, cangrelor was used almost exclusively in STEMI patients undergoing PCI. Even though cangrelor was used in high-risk patients, its use was associated with a low rate of stent thrombosis.
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Pereira, Naveen L., Michael E. Farkouh, Derek So, Ryan Lennon, Nancy Geller, Verghese Mathew, Malcolm Bell, et al. "Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention." JAMA 324, no. 8 (August 25, 2020): 761. http://dx.doi.org/10.1001/jama.2020.12443.
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Kitahara, Hideki, Kazuya Tateishi, Yuki Shiko, Yusuke Inaba, Yoshio Kobayashi, and Takahiro Inoue. "Comparison of short-term clinical outcomes between low-dose prasugrel and clopidogrel as part of triple antithrombotic therapy in patients requiring oral anticoagulant therapy and percutaneous coronary intervention." PLOS ONE 17, no. 7 (July 28, 2022): e0272140. http://dx.doi.org/10.1371/journal.pone.0272140.
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Background Triple antithrombotic therapy, including dual antiplatelet therapy and oral anticoagulant (OAC), is recommended for a short-term period after percutaneous coronary intervention (PCI) in patients requiring anticoagulation therapy. The purpose of this study was to compare in-hospital clinical outcomes between low-dose prasugrel (3.75 mg/day) and clopidogrel, as part of triple antithrombotic therapy, using a large database in Japan. Methods Patients with ischemic heart disease who underwent PCI between January 2015 and December 2019, and were prescribed triple therapy with aspirin, a P2Y12 inhibitor (clopidogrel or low-dose prasugrel), and OAC (direct oral anticoagulant: DOAC or vitamin K antagonist: VKA), were selected from the Diagnosis Procedure Combination database. The primary outcome was in-hospital mortality. The secondary outcomes were myocardial infarction, ischemic stroke, bleeding stroke, gastrointestinal bleeding, and blood transfusion. Results Overall, 5,777 patients were eligible in this analysis. The patients were divided into 4 subgroups according to the type of P2Y12 inhibitor and OAC: clopidogrel/DOAC (n = 1,628), clopidogrel/VKA (n = 1,334), prasugrel/DOAC (n = 1,607), and prasugrel/VKA (n = 1,208). There was no significant difference in the incidence of death and gastrointestinal bleeding among the 4 subgroups. The prasugrel/DOAC group had significantly lower incidence of MI (OR 0.566, 95% CI 0.348–0.921). The incidence of ischemic stroke was significantly lower in the prasugrel/DOAC group (OR 0.701, 95% CI 0.502–0.979), and significantly higher in the clopidogrel/VKA group (OR 1.680, 95% CI 1.273–2.216). Need for blood transfusion was less frequent in the prasugrel/DOAC group (OR 0.729, 95% CI 0.598–0.890), and more frequent in both the clopidogrel/VKA group (OR 1.424, 95% CI 1.187–1.708) and the prasugrel/VKA group (OR 1.633, 95% CI 1.367–1.950). Conclusions Combination of low-dose prasugrel and DOAC was associated with lower incidence of MI, ischemic stroke, and blood transfusion. Low-dose prasugrel may be feasible as part of triple therapy in patients undergoing PCI.
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Franchi, Francesco, Fabiana Rollini, Emilio Garcia, Jose Rivas Rios, Andrea Rivas, Malhar Agarwal, Megha Kureti, et al. "Effects of Edoxaban on the Cellular and Protein Phase of Coagulation in Patients with Coronary Artery Disease on Dual Antiplatelet Therapy with Aspirin and Clopidogrel: Results of the EDOX-APT Study." Thrombosis and Haemostasis 120, no. 01 (August 30, 2019): 083–93. http://dx.doi.org/10.1055/s-0039-1695772.
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AbstractIn patients requiring dual antiplatelet therapy (DAPT) who also have an indication to be treated with oral anticoagulant (OAC) drugs, aspirin withdrawal reduces the risk of bleeding. There is limited data on the pharmacodynamic effects associated with adding a nonvitamin K antagonist OAC on a background of aspirin and a P2Y12 inhibitor as well as dropping aspirin. Seventy-five patients on DAPT (aspirin plus clopidogrel) were randomized to DAPT plus high-dose edoxaban (60 mg once daily, Group A), DAPT plus low-dose edoxaban (30 mg once daily, Group B), or DAPT only (Group C) for 10 ± 2 days (Phase I). Afterwards, Groups A and B interrupted aspirin and maintained clopidogrel plus edoxaban for 10 ± 2 days, while patients in Group C maintained DAPT (Phase II). Platelet aggregation and clot kinetics were assessed at baseline, end of Phase I, and end of Phase II using thrombelastography (TEG), light transmittance aggregometry (LTA), VerifyNow P2Y12, and serum thromboxane-B2. The primary endpoint was the comparison of maximum amplitude (MA) measured by TEG, a measure of clot strength, between patients on DAPT plus high-dose edoxaban and patients on DAPT only. Edoxaban prolonged in a dose-dependent manner speed of thrombin generation (TEG R; Group A: 7.7 [6.8–8.7] vs. Group B: 7.4 [6.4–8.5] vs. Group C: 6.3 [5.7–7.0]; p = 0.05) but did not affect other markers of clot kinetics, including TEG MA (Group A: 63 [61–64] vs. Group B: 65 [63–67] vs. Group C: 64 [63–65]; p = 0.10). After aspirin discontinuation, platelet reactivity assessed by LTA using thrombin receptor activating peptide as agonist increased to a greater extent with low-dose edoxaban. Stopping aspirin did not affect markers of P2Y12 reactivity and had no or marginal effects on clot kinetics, but increased markers sensitive to cyclooxygenase-1 blockade.
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Aloia, Elio, Paolo Orselli, and Carlotta Sciaccaluga. "Triple Antithrombotic Therapy vs. Double Antithrombotic Therapy: One Scenario, 8 Questions, Many Conclusions." Current Cardiology Reviews 15, no. 3 (May 6, 2019): 219–23. http://dx.doi.org/10.2174/1573403x15666190111095438.
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In patients with atrial fibrillation undergoing percutaneous coronary intervention with the placement of stents, a triple antithrombotic therapy is empirically established, which consists of a combination of dual antithrombotic therapy (aspirin plus a P2Y12 inhibitor) and an oral anticoagulant agent. This choice is guided by the desirable result of reducing cerebrovascular and coronary ischemic events. However, there is an unwelcome outcome: an increased incidence of bleeding. On this matter, in 2018, a North American Perspective Update was published, about a year later it was followed by the publication of the European focus update on the dual antiplatelet therapy. After analysing the main differences between these two consensus documents, this review aims at examining the major studies on which they are based on, as a starting point to define the foundation of new trials that can help shed light on this prominent topic.
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Altoukhi, Renad M., Reema A. Alshouimi, Shahad M. Al Rammah, Mohammed Y. Alzahrani, Abdulaali R. Almutairi, Abdulmajeed M. Alshehri, Osamah M. Alfayez, Majed S. Al Yami, and Omar A. Almohammed. "Safety and efficacy of dual versus triple antithrombotic therapy (DAT vs TAT) in patients with atrial fibrillation following a PCI: a systematic review and network meta-analysis." BMJ Open 10, no. 9 (September 2020): e036138. http://dx.doi.org/10.1136/bmjopen-2019-036138.
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ObjectiveCreating an appropriate antithrombotic therapy for patients with atrial fibrillation (AF) who have undergone percutaneous coronary intervention (PCI) remains a dilemma. Several clinical trials compared the use of a dual antithrombotic therapy (DAT) regimen with a direct oral anticoagulants including (apixaban, dabigatran, edoxaban or rivaroxaban) and a P2Y12 inhibitor versus a triple antithrombotic therapy (TAT) that includes a vitamin K antagonist plus aspirin and a P2Y12 inhibitor in patients with AF who have undergone PCI. However, there are no head-to-head trials comparing the DAT regimens to each other. We aimed to compare the efficacy and safety of DAT regimens using a network meta-analysis (NMA) approach.DesignA systematic review and NMA of randomised clinical trials.MethodsWe conducted a systematic literature review to identify relevant randomised clinical trials and performed a Bayesian NMA for International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding, all-cause mortality, stroke, myocardial infarction (MI) and stent thrombosis outcomes. We used NetMetaXL V.1.6.1 and WinBUGS V.1.4.3 for the NMA and estimated the probability of ranking the treatments based on the surface under the cumulative ranking curve.ResultsThe comparison between DAT regimens showed no significant difference in the safety or efficacy outcomes. Apixaban regimen was ranked first as the preferred therapy in terms of ISTH major or CRNM bleeding and stroke, with a probability of 52% and 54%, respectively. Rivaroxaban regimen was the preferred therapy in terms of MI and stent thrombosis, with a probability of 34% and 27%, respectively. Dabigatran regimen was ranked first in terms of all-cause mortality, with a probability of 28%.ConclusionThe DAT regimens are as safe and effective as TAT regimens. However, ranking probabilities for the best option in the selected outcomes can be used to guide the selection among these agents based on different patients’ conditions.
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Lei, Yu, Bing Zhang, Dan Liu, Jian Zhao, Xiwen Dai, Jun Gao, Qing Mao, et al. "Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1 and P2Y12 as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor." Journal of Medicinal Chemistry 63, no. 24 (December 12, 2020): 15752–72. http://dx.doi.org/10.1021/acs.jmedchem.0c01524.
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Krishnamurthy, Arvindra, Claire Keeble, Michelle Anderson, Kathryn Somers, Natalie Burton-Wood, Charlotte Harland, Paul Baxter, et al. "Real-world comparison of clopidogrel, prasugrel and ticagrelor in patients undergoing primary percutaneous coronary intervention." Open Heart 6, no. 1 (June 2019): e000951. http://dx.doi.org/10.1136/openhrt-2018-000951.
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BackgroundThere is a paucity of real-world outcome data comparing clopidogrel, prasugrel and ticagrelor in primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI). We sought to assess the association of choice of oral P2Y12-receptor inhibitor with clinical outcomes following PPCI for STEMI in a large consecutive patient series.MethodsDemographic, procedural and 12-month outcome data were prospectively collected for all patients undergoing PPCI in Leeds, UK, between 01 January 2009 and 31 December 2011, and 01 January 2013 and 31 December 2013. Clinical endpoints were 30-day and 12-month all-cause mortality, recurrent MI and 30-day HORIZONS-major bleeding. Logistic regression analyses were undertaken to adjust for confounding factors.ResultsPrasugrel (n=1244) was associated with lower adjusted 30-day (OR 0.53 (0.34–0.85)) and 12-month (OR 0.55 (0.38–0.78)) mortality, and 12-month MI (OR 0.63 (0.42–0.94)) compared with clopidogrel (n=1648). Importantly, prasugrel was associated with lower adjusted 30-day mortality (OR 0.51 (0.29–0.91)) compared with ticagrelor (n=811). Lower 30-day (OR 0.40 (0.17–0.94)) and 12-month (OR 0.54 (0.32–0.93)) MI were observed in ticagrelor compared with clopidogrel, an association absent in comparison with prasugrel. Adjusted bleeding were not statistically significantly different among the P2Y12-receptor inhibitors.ConclusionIn this large consecutive real-world series, prasugrel was associated with lower adjusted 30-day mortality compared with ticagrelor and clopidogrel, and lower adjusted 12-month mortality compared with clopidogrel. Both prasugrel and ticagrelor were associated with lower recurrent MI following PPCI compared with clopidogrel, with no overall increase in adjusted bleeding.
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Goette, Andreas, and Pascal Vranckx. "Atrial fibrillation patients undergoing percutaneous coronary intervention: dual or triple antithrombotic therapy with non-vitamin K antagonist oral anticoagulants." European Heart Journal Supplements 22, Supplement_I (September 1, 2020): I22—I31. http://dx.doi.org/10.1093/eurheart/suaa101.
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Abstract About 20% of all atrial fibrillation (AF) patients develop coronary artery disease, which requires coronary stenting [percutaneous coronary intervention (PCI)]. Thus, this subcohort of AF patients may require aggressive antithrombotic therapy encompassing vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulants (NOAC) plus aspirin and a P2Y12 inhibitor. At present, four clinical Phase IIIb trials using dabigatran, rivaroxaban, apixaban, or edoxaban, were published. These studies assessed the impact of NOACs as a part of DAT therapy vs. triple therapy. Compared with triple therapy, NOAC-based DAT has been shown to be associated with reduced major bleeding as well as intracranial haemorrhages. The benefit, however, is somewhat counterbalanced by a higher risk of stent-related ischaemia during the early phase of dual therapy. Thus, triple therapy after stenting is appropriate for at least 14 days with a maximum of 30 days. Thereafter, DAT including a NOAC is the therapy of choice in AF PCI patients to reduce the risk of bleeding during a 1 year of follow-up compared to VKA-based regimes. The present review summarizes the published study results and demonstrates differences in trial design and reported outcomes.
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Barańska, Malwina, Adam Sikora, Katarzyna Buszko, Emilia Siemińska, Michał Piotr Marszałł, Jolanta Siller-Matula, Bernd Jilma, et al. "Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina." Thrombosis and Haemostasis 117, no. 04 (2017): 718–26. http://dx.doi.org/10.1160/th16-08-0670.
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SummaryOral administration of crushed ticagrelor tablets turned out to be an efficacious method that improves its pharmacokinetics and pharmacodynamics. This strategy, however, is unlikely to eliminate the drug-drug interaction in patients receiving intravenous morphine, as the impairment of the P2Y12 inhibitor absorption related to decreased propulsive motility of the gastro-intestinal tract is the most likely mechanism of interaction. Thus, we designed a pharmacokinetic and pharmacodynamic study setting the feasibility of platelet inhibition with a loading dose of ticagrelor given as crushed tablets sublingually compared with two other ticagrelor loading dose administration strategies: integral tablet given orally and crushed tablet given orally in patients with unstable angina. Ticagrelor and its metabolite AR-C124900XX plasma concentration was evaluated in nine time points (time frame of 6 hours) using liquid chromatography coupled with mass spectrometry; platelet reactivity was evaluated using multiple electrode aggregometry. The area under the plasma concentration-time curve for ticagrelor and AR-C124900XX was significantly higher in patients treated with crushed tablets given orally compared with crushed tablets given sublingually only within the first hour after loading dose (936.9 ± 898.0 vs 368.0 ± 422.4, p=0.042 and 103.4 ± 120.8 vs 31.3 ± 43.9, p=0.031, respectively). Moreover, we showed significantly stronger platelet inhibition in patients receiving crushed ticagrelor orally vs. sublingually at 30 and 45 min after the loading dose (p=0.024 and p=0.016, respectively). Therefore, the administration strategy of ticagrelor determines the pharmacokinetic and pharmacodynamic profile of both ticagrelor and its active metabolite AR-C124900XX.
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Penna, Claudia, Manuela Aragno, Alessia Sofia Cento, Saveria Femminò, Isabella Russo, Federica Dal Bello, Fausto Chiazza, et al. "Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades." Oxidative Medicine and Cellular Longevity 2020 (August 4, 2020): 1–12. http://dx.doi.org/10.1155/2020/9219825.
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Inhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protection induced by the P2Y12 receptor antagonist Ticagrelor. Ticagrelor (150 mg/kg) was orally administered to rats for three consecutive days. Then, isolated hearts underwent an ischemia/reperfusion (30 min ischemia/60 min reperfusion; IR) protocol. The selective NLRP3 inflammasome inhibitor INF (50 μM) was infused before the IR protocol to the hearts from untreated animals or pretreated with Ticagrelor. In parallel experiments, the hearts isolated from untreated animals were perfused with Ticagrelor (3.70 μM) before ischemia and subjected to IR. The hearts of animals pretreated with Ticagrelor showed a significantly reduced infarct size (IS, 49±3% of area at risk, AAR) when compared to control IR group (69±2% of AAR). Similarly, ex vivo administration of INF before the IR injury resulted in significant IS reduction (38±3% of AAR). Myocardial IR induced the NLRP3 inflammasome complex formation, which was attenuated by either INF pretreatment ex vivo, or by repeated oral treatment with Ticagrelor. The beneficial effects induced by either treatment were associated with the protective Reperfusion Injury Salvage Kinase (RISK) pathway activation and redox defence upregulation. In contrast, no protective effects nor NLRP3/RISK modulation were recorded when Ticagrelor was administered before ischemia in isolated heart, indicating that Ticagrelor direct target is not in the myocardium. Our results confirm that Ticagrelor conditioning effects are likely mediated through platelets, but are not additives to the ones achieved by directly inhibiting NLRP3.
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Wang, Qiang, and Keping Yang. "Dual therapy with an oral non-vitamin K antagonist and a P2Y12 inhibitor vs triple therapy with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus patients with co-existing atrial fibrillation following percutaneous coronary intervention." Medicine 100, no. 15 (April 16, 2021): e25546. http://dx.doi.org/10.1097/md.0000000000025546.
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