Ticagrelor in Acute Coronary Syndromes

<p>The PLATO trial demonstrated significantly lower mortality and myocardial infarction in acute coronary syndrome (ACS) patients treated with ticagrelor and aspirin compared to clopidogrel and aspirin. Ticagrelor is a direct acting P2Y12 receptor antagonist, and is a more potent inhibitor of platelet reactivity than clopidogrel, and this is believed to be the main cause of its superior efficacy in the PLATO trial. A range of factors have been associated with high on-treatment platelet reactivity (HOTPR) on clopidogrel, including genetic factors, drug interactions and clinical risk factors. HOTPR on clopidogrel has been associated with a higher risk of adverse outcomes following ACS. On the basis of the PLATO trial results, and the theoretical limitations associated with clopidogrel, ticagrelor was funded by PHARMAC in July 2013, and has been recommended for use in patients with ACS in New Zealand. This thesis examined the use of ticagrelor in a real world ACS population being managed through Wellington Hospital cardiology department. We examined platelet reactivity in patients treated with ticagrelor compared to clopidogrel, factors associated with clinician choice to use ticagrelor versus clopidogrel and the incidence of side effects of ticagrelor that may have implications for compliance with the drug outside the setting of a randomized controlled trial. We found that ticagrelor significantly reduced both platelet reactivity (30.3 AU ± 17.5 versus 43.7 AU ± 24.8, p= 0.0001) and the proportion of patients classified as having HOTPR (15.9% versus 37.7%, p= 0.0001), in comparison to clopidogrel. The clinical variables associated with HOTPR differ between clopidogrel and ticagrelor, suggesting that different factors were driving residual platelet reactivity on the two agents. Over a 2 year period, clopidogrel (68%) was used more commonly than ticagrelor (42%), and in a different cohort of patients. Patients treated with ticagrelor were younger (61 years ± 10 versus 65 years ± 12, p=0.0001), less likely to present with STEMI (12% versus 31%, p=0.0001), less likely to have a history of prior myocardial infarction (15.8% versus 22.7%, p=0.05), and had lower GRACE (98 ± 24 versus 108 ± 28, p=0.0001) and CRUSADE (25 ± 9 versus 28 ± 12, p=0.001) risk scores compared to those treated with clopidogrel. Prescription of ticagrelor was therefore not driven by clinical risk. Antiplatelet prescription varied significantly according to the patients’ admitting hospital. Bleeding rates on ticagrelor and clopidogrel within 30 days of study enrolment were low and were not significantly different. There was 1 patient on clopidogrel who had the drug discontinued due to bleeding. At 30 day follow up, significantly more patients treated with ticagrelor reported dyspnoea (43.3% versus 27.1%, p=0.001), however discontinuation of the drug due to dyspnoea on ticagrelor was infrequent (1.7%). In this real world cohort of ACS patients, we observed that ticagrelor was associated with more potent platelet inhibition than clopidogrel, but was not associated with factors leading to increased discontinuation at 30 days. Despite the proven benefits of ticagrelor compared to clopidogrel, the majority of patients, including the highest risk patients appear to be preferentially treated with clopidogrel. The causes contributing to underuse of ticagrelor need to be examined and addressed.</p>

Ticagrelor in Acute Coronary Syndromes

<p>The PLATO trial demonstrated significantly lower mortality and myocardial infarction in acute coronary syndrome (ACS) patients treated with ticagrelor and aspirin compared to clopidogrel and aspirin. Ticagrelor is a direct acting P2Y12 receptor antagonist, and is a more potent inhibitor of platelet reactivity than clopidogrel, and this is believed to be the main cause of its superior efficacy in the PLATO trial. A range of factors have been associated with high on-treatment platelet reactivity (HOTPR) on clopidogrel, including genetic factors, drug interactions and clinical risk factors. HOTPR on clopidogrel has been associated with a higher risk of adverse outcomes following ACS. On the basis of the PLATO trial results, and the theoretical limitations associated with clopidogrel, ticagrelor was funded by PHARMAC in July 2013, and has been recommended for use in patients with ACS in New Zealand. This thesis examined the use of ticagrelor in a real world ACS population being managed through Wellington Hospital cardiology department. We examined platelet reactivity in patients treated with ticagrelor compared to clopidogrel, factors associated with clinician choice to use ticagrelor versus clopidogrel and the incidence of side effects of ticagrelor that may have implications for compliance with the drug outside the setting of a randomized controlled trial. We found that ticagrelor significantly reduced both platelet reactivity (30.3 AU ± 17.5 versus 43.7 AU ± 24.8, p= 0.0001) and the proportion of patients classified as having HOTPR (15.9% versus 37.7%, p= 0.0001), in comparison to clopidogrel. The clinical variables associated with HOTPR differ between clopidogrel and ticagrelor, suggesting that different factors were driving residual platelet reactivity on the two agents. Over a 2 year period, clopidogrel (68%) was used more commonly than ticagrelor (42%), and in a different cohort of patients. Patients treated with ticagrelor were younger (61 years ± 10 versus 65 years ± 12, p=0.0001), less likely to present with STEMI (12% versus 31%, p=0.0001), less likely to have a history of prior myocardial infarction (15.8% versus 22.7%, p=0.05), and had lower GRACE (98 ± 24 versus 108 ± 28, p=0.0001) and CRUSADE (25 ± 9 versus 28 ± 12, p=0.001) risk scores compared to those treated with clopidogrel. Prescription of ticagrelor was therefore not driven by clinical risk. Antiplatelet prescription varied significantly according to the patients’ admitting hospital. Bleeding rates on ticagrelor and clopidogrel within 30 days of study enrolment were low and were not significantly different. There was 1 patient on clopidogrel who had the drug discontinued due to bleeding. At 30 day follow up, significantly more patients treated with ticagrelor reported dyspnoea (43.3% versus 27.1%, p=0.001), however discontinuation of the drug due to dyspnoea on ticagrelor was infrequent (1.7%). In this real world cohort of ACS patients, we observed that ticagrelor was associated with more potent platelet inhibition than clopidogrel, but was not associated with factors leading to increased discontinuation at 30 days. Despite the proven benefits of ticagrelor compared to clopidogrel, the majority of patients, including the highest risk patients appear to be preferentially treated with clopidogrel. The causes contributing to underuse of ticagrelor need to be examined and addressed.</p>

TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia

The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss?of?function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD). Because abnormalities in Ca2+ signaling have been observed in several AD models, we investigated TREM2 regulation of Ca2+ signaling via genetic deletion in human induced pluripotent stem cell-derived microglia (iPSC microglia). We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca2+ signals in response to purinergic agonists such as ADP that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y12 and P2Y13 receptors, results in sustained Ca2+ influx and alters cell motility and process extension in TREM2 KO microglia. In a 'Ca2+ clamp' assay using iPSC-microglia expressing the genetically encoded Ca2+ probe, Salsa6f, we found that cytosolic Ca2+ tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca2+ using a P2Y12 receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca2+ response to purinergic signals, suggesting a window of Ca2+ signaling for optimal microglial motility.

The P2Y12 Receptor Antagonist Ticagrelor Ameliorates Pulmonary Hypertension

Background: Pulmonary arterial hypertension (PAH) is a disease that the pulmonary artery is abnormally elevated. P2Y12 is an adenosine diphosphate (ADP) receptor and it act as the target of thienopyridine antiplatelet drugs by controlling vascular remodeling. Inhibition of P2Y12 receptor in the process of PAH was explored in this study.Methods: The PAH model was established in Sprague-Dawley rats by single subcutaneous injection of 60 mg/kg monocrotaline (MCT). The ticagrelor solution (a selective P2Y12R inhibitor) was intraperitoneally injected into rats at a dose of 14 mg/kg from the time of MCT injection to day 28.Results: In the lung tissues of PAH rats, the marked P2Y12R was detected. Treatment with ticagrelor greatly decreased P2Y12R level and efficiently abolished the upregulation of α-SMA as demonstrated by Western blot and RT-PCR. The wall thickness and occlusion score of the pulmonary arterioles showed that blockade of P2Y12R could relieve lung remodeling caused by PAH. The haemodynamic changes at 4 weeks determined that P2Y12R inhibition affected RV pressure and right heart hypertrophy.Conclusions: P2Y12R might be involved in the pathogenesis of PAH. Blockade of P2Y12R has potential in treating PAH.

Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

Main Recommendations 1 ESGE recommends that the initial assessment of patients presenting with acute lower gastrointestinal bleeding should include: a history of co-morbidities and medications that promote bleeding; hemodynamic parameters; physical examination (including digital rectal examination); and laboratory markers. A risk score can be used to aid, but should not replace, clinician judgment.Strong recommendation, low quality evidence. 2 ESGE recommends that, in patients presenting with a self-limited bleed and no adverse clinical features, an Oakland score of ≤ 8 points can be used to guide the clinician decision to discharge the patient for outpatient investigation.Strong recommendation, moderate quality evidence. 3 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and no history of cardiovascular disease, a restrictive red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 7 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of 7–9 g/dL is desirable.Strong recommendation, low quality evidence. 4 ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and a history of acute or chronic cardiovascular disease, a more liberal red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 8 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of ≥ 10 g/dL is desirable.Strong recommendation, low quality evidence. 5 ESGE recommends that, in patients with major acute lower gastrointestinal bleeding, colonoscopy should be performed sometime during their hospital stay because there is no high quality evidence that early colonoscopy influences patient outcomes.Strong recommendation, low quality of evidence. 6 ESGE recommends that patients with hemodynamic instability and suspected ongoing bleeding undergo computed tomography angiography before endoscopic or radiologic treatment to locate the site of bleeding.Strong recommendation, low quality evidence. 7 ESGE recommends withholding vitamin K antagonists in patients with major lower gastrointestinal bleeding and correcting their coagulopathy according to the severity of bleeding and their thrombotic risk. In patients with hemodynamic instability, we recommend administering intravenous vitamin K and four-factor prothrombin complex concentrate (PCC), or fresh frozen plasma if PCC is not available.Strong recommendation, low quality evidence. 8 ESGE recommends temporarily withholding direct oral anticoagulants at presentation in patients with major lower gastrointestinal bleeding.Strong recommendation, low quality evidence. 9 ESGE does not recommend withholding aspirin in patients taking low dose aspirin for secondary cardiovascular prevention. If withheld, low dose aspirin should be resumed, preferably within 5 days or even earlier if hemostasis is achieved or there is no further evidence of bleeding.Strong recommendation, moderate quality evidence. 10 ESGE does not recommend routinely discontinuing dual antiplatelet therapy (low dose aspirin and a P2Y12 receptor antagonist) before cardiology consultation. Continuation of the aspirin is recommended, whereas the P2Y12 receptor antagonist can be continued or temporarily interrupted according to the severity of bleeding and the ischemic risk. If interrupted, the P2Y12 receptor antagonist should be restarted within 5 days, if still indicated.Strong recommendation, low quality evidence.

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor

Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at t max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.

DNA Damage in AML-12 Hepatocytes and 3T3-L1 Adipocytes Treated with Clopidogrel

Background: Clopidogrel has been commonly prescribed as a selective P2Y12 receptor antagonist to reduce heart attack and stroke risk. Nearly 10 % of absorbed clopidogrel is metabolized by cytochrome P450 (CYP) enzymes in the liver to active forms and 90 % to inactive clopidogrel carboxylate by esterases. Objective: Since different forms of clopidogrel have cytotoxic potential, our aim was to determinate the effect of clopidogrel (7.5, 40 and 75µM) over DNA damage in adipocyte and hepatocytes. Material Methods: In the present study DNA damage was investigated by Comet analysis using 3T3-L1 adipocytes and Alpha Mouse 12 (AML-12) hepatocytes. Results: DNA fragmentation was found to be increased as a response to 7.5 µM, 40 µM and 75 µM clopidogrel treatment compared to non-treated control groups in AML-12 hepatocytes (p<0.01, p<0.001, p<0.01 respectively) and 3T3-L1 adipocytes (p<0.001, p<0.001 and p<0.001 respectively). DNA damage levels as a response to clopidogrel treatment was found to be higher in 3T3-L1 adipocytes than AML-12 hepatocytes. Also, DNA damage levels in adipocytes and hepatocytes were found to increase dose dependently for 7.5 and 40 μM clopidogrel whereas decreased as a response to 75 μM. Conclusion: According to our results, clopidogrel results in more DNA damage in adipocytes than in hepatocytes. The molecular mechanism of clopidogrel genotoxicity need to be further investigated especially in adipose tissue.