Ticagrelor-Related Dyspnea Beyond Adenosine: Insights into Retrotrapezoid Hyperactivity.

Ticagrelor, a P2Y12 receptor antagonist, has been demonstrated to induce dyspnea, which is not associated with cardiac or pulmonary alterations, or metabolic disturbances. The attribution of ticagrelor-related dyspnea to excess adenosine has been widely proposed, yet is not supported by experimental data. In this paper, we put forth a novel hypothesis that the hyperactivity of the retrotrapezoid nucleus, a group of ventral medullary neurons involved in respiratory modulation, is the underlying cause of ticagrelor-related dyspnea. This hypothesis offers a theoretical resolution to the discrepancies and controversies present in previous theories.

Supporting appropriate use of extended dual antiplatelet therapy post-myocardial infarction based on an innovative 12-month ticagrelor virtual service.

Purpose: Extended dual antiplatelet therapy (DAPT) with ticagrelor and aspirin is recommended in selected cases after myocardial infarction (MI) but not widely deployed in practice. This study assessed an innovative, cardiology pharmacist-led virtual service for determining eligibility for extended DAPT among patients completing 12 months of initial DAPT in primary care following MI. Methods: Within this model, potentially eligible individuals are reviewed virtually by a cardiology pharmacist for suitability for extended DAPT with reduced-dose ticagrelor [60 mg twice daily (BD)] for up to 3 years. Eligibility is guided by the PEGASUS-TIMI 54 trial criteria (aged ≥50 years and having ≥1 high-risk feature for further ischaemic events). This is balanced against potential ineligibility driven primarily by bleeding risk, assessed using PRECISE-DAPT score. The final recommendation is sent to primary care to action. The present work is a retrospective evaluation of patients referred to the service between July 2018 and December 2021. Results: A total of 200 patients were included [n = 131 (65.5%) male; mean age: 69.4 ± 9.5 years]. Of these, 79 (39.5%) were recommended for extended DAPT based on the balance of risks for further ischaemic events vs. bleeding. Sixty-three patients on high-dose DAPT (ticagrelor 90 mg BD)-which is inappropriate beyond 12 months-were reassigned to reduced-dose DAPT or aspirin monotherapy. Conclusions: This virtual clinic played a key role in medicines optimisation, enabling appropriate patients to benefit from extended DAPT while offsetting bleeding risk. The model could be adapted locally for use elsewhere.

Timing of P2Y12 Inhibitor Administration in Patients With STEMI Undergoing Primary PCI.

BACKGROUND: The optimal timing of P2Y12 inhibitor administration in patients with ST-segment elevation myocardial infarction (STEMI) has not been completely elucidating. OBJECTIVES: This analysis from a prospective multicenter registry sought to assess the safety and effectiveness of P2Y12 inhibitor pretreatment in patients transferred for primary percutaneous coronary intervention (PCI) within a regional STEMI network. METHODS: Pretreatment was defined as P2Y12 inhibitor administration before coronary angiography. Endpoints were major adverse cardiac events (MACE), major bleeding, and net adverse clinical events, a composite of MACE or major bleeding, within 30 days of index admission. Association of P2Y12 inhibitor pretreatment with outcomes was modeled using doubly robust weighted estimators based on propensity score analysis. RESULTS: Of 1,624 patients included, 1,033 received P2Y12 inhibitors before angiography and 591 in the catheterization laboratory (cath lab). The non-pretreated cohort more often had history of coronary artery disease and were more likely to receive antiplatelet therapy before the index admission. After adjustment for confounding and dependent censoring, pretreatment with P2Y12 inhibitors predicted lower risk of MACE (adjusted HR: 0.53; 95% CI: 0.37-0.76), without increasing bleeding risk (adjusted HR: 0.62; 95% CI: 0.36-1.05), resulting in superior net clinical benefit (adjusted HR: 0.47; 95% CI: 0.26-0.86) compared with in-cath lab administration of P2Y12 inhibitors. There was a significant treatment-by-time interaction for MACE risk, whereby the observed benefits of pretreatment only became apparent when time between P2Y12 inhibitor administration and PCI was longer than 80 minutes. CONCLUSIONS: In contemporary patients with STEMI transferred for primary PCI, pretreatment with P2Y12 inhibitors was associated with a significant time-dependent reduction of 30-day MACE without increasing bleeding risk.

Dual antithrombotic therapy dose-dependently alters hemostatic plug structure and function.

BACKGROUND: Antithrombotic medications carry an inherent risk of bleeding, which may be exacerbated when anticoagulant and antiplatelet therapeutics are combined. Prior studies have shown different effects of antiplatelet vs anticoagulant drugs on the structure and function of hemostatic plugs in vivo. OBJECTIVES: We examined whether dual antithrombotic treatment consisting of combined antiplatelet and anticoagulant therapeutics alters hemostatic plug structure and function differently from treatment with either therapeutic alone. METHODS: Mice were treated with the P2Y12 antagonist clopidogrel and the factor Xa inhibitor rivaroxaban across a range of doses, either alone or in combination. The hemostatic response was assessed using a mouse jugular vein puncture injury model. Platelet accumulation and fibrin deposition were evaluated using quantitative multiphoton fluorescence microscopy, and bleeding times were recorded. RESULTS: Mice treated with clopidogrel alone exhibited a decrease in platelet accumulation at the site of injury, with prolonged bleeding times only at the highest doses of clopidogrel used. Mice treated with rivaroxaban alone instead showed a reduction in fibrin deposition with no impact on bleeding. Mice treated with both clopidogrel and rivaroxaban exhibited platelet and fibrin accumulation that was similar to that with either drug given alone; however, dual antithrombotic therapy resulted in impaired hemostasis at doses that had no impact on bleeding when given in isolation. CONCLUSION: Combined administration of antiplatelet and anticoagulant therapeutics exacerbates bleeding as compared to that with either drug alone, potentially via combined loss of both adenosine 5'-diphosphate- and thrombin-mediated platelet activation. These findings enhance our understanding of the bleeding risk associated with dual antithrombotic therapy.

Ticagrelor Can Regulate the Ion Channel Characteristics of Superior Cervical Ganglion Neurons after Myocardial Infarction.

BACKGROUND: The superior cervical ganglion (SCG) plays a key role in cardiovascular diseases. The aim of this study was to determine the changes in the ion channel characteristics of the SCG following myocardial infarction (MI) and the role of pretreatment with the P2Y12 receptor antagonist ticagrelor (TIC). METHODS: A total of 18 male rabbits were randomly divided into a control group, MI group, and P2Y12 receptor antagonist (TIC) group (abbreviated as the TIC group). Rabbit MI was performed via two abdominal subcutaneous injections of 150 mg·kg-1·d-1 of isoproterenol (ISO) with an interval of 24 h. TIC pretreatment at 20 mg·kg-1·d-1 was administered via gavage for two consecutive days. The cardiac function of each group was evaluated with echocardiography. ADP receptor P2Y12 expressions in SCGs were determined using RT-PCR and immunofluorescence staining. Ion channel characteristics of SCG neurons were measured using a whole-cell patch clamp. Intracellular calcium concentrations for SCG neurons were measured using confocal microscopy. RESULTS: Cardiac function was reduced in the rabbits of the MI group, the sympathetic nerve activity of SCGs was increased, and the current amplitude of the neuron ion channel was increased. MI led to alterations in the activation and inactivation characteristics of INa channels accompanied by increased expression of P2Y12 in SCGs. Most of these abnormalities were prevented by TIC pretreatment in the TIC group. CONCLUSIONS: TIC pretreatment could attenuate the increase in P2Y12 expression in SCGs and the changes to the ion channel characteristics of SCG neurons after MI. This may be the mechanism underlying the cardiac protective effects of TIC.

GP IIb/IIIa Receptor Inhibitors in Mechanically Ventilated Patients with Cardiogenic Shock due to Myocardial Infarction in the Era of Potent P2Y12 Receptor Antagonists.

Objective: To investigate the association between GP IIb/IIIa receptor inhibitors (GPI) and mortality and bleeding in patients with cardiogenic shock (CS) due to myocardial infarction (MI) who were mechanically ventilated on admission. Methods: We retrospectively divided 153 patients into two groups (with or without GPI). Thirty-day and one-year all-cause mortality and bleeding were studied. Results: The observed 30-day and one-year all-cause mortality were similar in both groups [54 (69.2%) with GPI vs. 62 (82.7%) without GPI; p = 0.06, and 60 (76.9%) with GPI vs. 64 (85.3%) without GPI; p = 0.22, respectively]. Patients with GPI suffered fewer unsuccessful PCI (TIMI 0/1 was 10% in the GPI group vs. 57% in the group without GPI), experienced more improvements in TIMI ≥ 1 flow [68 (87.2%) in the GPI group vs. 38 (50.7%) without GPI; p < 0.0001], and they achieved better cerebral performance category (CPC) scores (1.61 ± 0.99 with GPI vs. 2.76 ± 1.64 without GPI; p = 0.005). The bleeding rate was similar in patients with and without GPI [33 (42.3%) vs. 31 (41.3%): p = 1.00], in patients with P2Y12 receptor antagonists (P2Y12) [18 (46.1%) with GPI vs. 21 (46.7%) without GPI; p = 1.00], and in patients with potent P2Y12 [8 (30.8%) with GPI vs. 9 (37.5%) without GPI; p = 0.77]. Conclusions: Due to the study design (limited sample size, retrospective inclusion with high risk of selection bias), our analysis does not allow us to draw conclusions about the effectiveness of GPI in this context. Despite all these limitations, GPI were associated with improved TIMI flow after PCI in our multivariable model without increasing bleeding rates. In addition, better CPC scores were observed, but no association between GPI and outcome was found. Our analysis suggests that selective use of GPI may be beneficial in mechanically ventilated patients with MI in CS without additional bleeding risk, even in the era of potent P2Y12.

Antiplatelet Therapy Aims and Strategies in Asian Patients with Acute Coronary Syndrome or Stable Coronary Artery Disease.

Dual antiplatelet therapy (DAPT) has been the mainstay treatment to reduce ischemic events, such as myocardial infarction or stroke, in patients with coronary artery disease (CAD). The development of potent P2Y12 inhibitors (ticagrelor and prasugrel) has helped to further reduce ischemic events, particularly among high-risk patients. Meanwhile, the evolution of newer generations of drug-eluting stents are also improving outcomes of percutaneous coronary intervention. Research studies on antiplatelet therapy in recent years have focused on balancing ischemic and bleeding risks through different strategies, which include P2Y12 inhibitor monotherapy, escalation and de-escalation, and extended DAPT. Because results from the large number of clinical studies may sometimes appear conflicting, this review aims to summarize recent advances, and demonstrate that they are aligned by a general principle, namely, strategies may be adopted based on treatment aims for specific patients at several time points. Another aim of this review is to outline the important considerations for using antiplatelet therapy in Asian patients, in whom there is a greater prevalence of CYP2C19 loss-of-function mutations, and a common increased risk of bleeding, despite high platelet reactivity (the so-called "East Asian Paradox").

The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration.

Here, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma in vitro demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the ex vivo evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration.

Ischemic Events Occur Early in Patients Undergoing Percutaneous Coronary Intervention and Are Reduced With Cangrelor: Findings From CHAMPION PHOENIX.

BACKGROUND: Thrombotic events are reduced with cangrelor, an intravenous P2Y12 inhibitor. We sought to characterize the timing, number, and type of early events (within 2 hours of randomization) in CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). METHODS: CHAMPION PHOENIX was a double-blind, placebo-controlled trial that randomized patients undergoing percutaneous coronary intervention to cangrelor or clopidogrel. For this analysis, we evaluated the efficacy of cangrelor in the first 2 hours postrandomization with regards to the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis). Sensitivity analyses were performed evaluating a secondary, post hoc end point (death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis). RESULTS: The majority of events (63%) that occurred in the trial occurred within 2 hours of randomization. The most common early event was myocardial infarction; next were stent thrombosis, ischemia driven revascularization, and death. In the first 2 hours after randomization, cangrelor significantly decreased the primary composite end point compared with clopidogrel (4.1% versus 5.4%; hazard ratio, 0.76 [95% CI, 0.64-0.90], P=0.002). Similar findings were seen for the composite end point of death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium stent thrombosis at 2 hours (0.9% versus 1.6%; hazard ratio, 0.57 [95% CI, 0.40-0.80], P=0.001). Between 2 and 48 hours, there was no difference in the primary composite end point (0.6% versus 0.5%; odds ratio, 1.17 [95% CI, 0.71-1.93]; P=0.53). Early (≤2 hours of randomization) GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate or severe bleeding events were infrequent, and there was no significant difference with cangrelor compared with clopidogrel (0.2% [n=10] versus 0.1% [n=4]; adjusted odds ratio, 1.41 [95% CI, 0.37-5.40]; P=0.62). CONCLUSIONS: The reductions in ischemic events and overall efficacy seen with cangrelor in CHAMPION PHOENIX occurred early and during the period of time in which patients were being actively treated with cangrelor. These findings provide evidence that supports the importance of potent platelet inhibition during percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01156571.