ticagrelor and Diabetes-Mellitus--Type-2

Cardiometabolic diseases lead to vascular complications, which cause increasing morbidity and mortality worldwide. The underlying mechanisms are multifactorial and complex but may involve altered purinergic signaling that significantly contributes to cardiovascular dysfunction. Ticagrelor is a successful purinergic drug directly targeting ADP-mediated P2Y

Topics: Adenosine; Adenosine Triphosphate; Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Erythrocytes; Humans; Purinergic Agonists; Signal Transduction; Ticagrelor

Type 2 diabetes (T2D) is associated with several abnormalities in haemostasis predisposing to thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy.

Topics: Adenosine; Adenosine Monophosphate; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Diabetes Mellitus, Type 2; Drug Resistance; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Factors; Ticagrelor; Ticlopidine; Treatment Outcome

Ticagrelor (P2Y12 receptor antagonist) is presently indicated for preventing atherothrombotic events in patients with acute coronary syndrome and patients with a history of myocardial infarction. The PARTHENON clinical development program comprises five randomized, controlled, cardiovascular, indication-seeking outcome studies, aiming to evaluate ticagrelor across the spectrum of patients with atherothrombotic disease. Results of two large-scale trials support a benefit for ticagrelor in patients with acute coronary syndrome (PLATO; ClinicalTrials.gov: NCT00391872) and in patients with a history of myocardial infarction (PEGASUS-TIMI 54; ClinicalTrials.gov: NCT01225562). Ongoing trials will provide information on the efficacy and safety of ticagrelor in patients with acute ischemic stroke or transient ischemic attack (SOCRATES; ClinicalTrials.gov: NCT01994720), peripheral artery disease (EUCLID; ClinicalTrials.gov: NCT01732822) and coronary artery disease in patients with Type 2 diabetes mellitus (THEMIS: ClinicalTrials.gov: NCT01991795).

Topics: Acute Coronary Syndrome; Adenosine; Atherosclerosis; Diabetes Mellitus, Type 2; Humans; Myocardial Infarction; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Ticagrelor; Treatment Outcome

THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry.. The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy.. In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.'. http://www.. gov identifier: NCT01991795.

Topics: Aspirin; Coronary Artery Disease; Diabetes Mellitus, Type 2; Humans; Myocardial Infarction; Outcome Assessment, Health Care; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Stroke; Ticagrelor; Treatment Outcome

To conduct a health economic evaluation of ticagrelor in patients with type 2 diabetes and coronary artery disease (CAD) from a multinational payer perspective. Cost-effectiveness and cost-utility of ticagrelor were evaluated in the overall effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS) trial population and in the predefined patient group with prior percutaneous coronary intervention.. A Markov model was developed to extrapolate patient outcomes over a lifetime horizon. The primary outcome was incremental cost-effectiveness ratios (ICERs), which were compared with conventional willingness-to-pay thresholds [€47 000/quality-adjusted life-year (QALY) in Sweden and €30 000/QALY in other countries].Treatment with ticagrelor resulted in QALY gains of up to 0.045 in the overall population and 0.099 in patients with percutaneous coronary intervention (PCI). Increased costs and benefits translated to ICERs ranged between €27 894 and €42 252/QALY across Sweden, Germany, Italy, and Spain in the overall population. In patients with prior PCI, estimated ICERs improved to €18 449, €20 632, €20 233, and €13 228/QALY in Sweden, Germany, Italy, and Spain, respectively, driven by higher event rates and treatment benefit.. Based on THEMIS results, ticagrelor plus aspirin compared with aspirin alone may be cost-effective in some European countries in patients with T2DM and CAD and no prior myocardial infarction (MI) or stroke. Additionally, ticagrelor is likely to be cost-effective across European countries in patients with a history of PCI.

Topics: Aspirin; Coronary Artery Disease; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Humans; Percutaneous Coronary Intervention; Ticagrelor

THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA. In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors.. Outcomes were analyzed across baseline diabetes duration, HbA. In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA. Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population.

Topics: Aspirin; Coronary Artery Disease; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Retrospective Studies; Ticagrelor; Treatment Outcome

Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear.. In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.. A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02).. In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).

Topics: Aged; Aspirin; Coronary Artery Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Stroke; Ticagrelor; Treatment Outcome

Topics: Aged; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Male; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Stroke; Ticagrelor

In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients ≥50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of ≥50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.

Topics: Aged; Aspirin; Clinical Trials, Phase III as Topic; Coronary Artery Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Ticagrelor; Time Factors; Treatment Outcome

Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM).. Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s. We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25).. Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.

Topics: Aged; Aged, 80 and over; Blood Flow Velocity; Blood Viscosity; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Lower Extremity; Male; Microcirculation; Middle Aged; New York City; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Regional Blood Flow; Ticagrelor; Time Factors; Treatment Outcome

Patients with type 2 diabetes mellitus (T2DM) are at higher risk of thrombotic complications. Studies have indicated that patients with T2DM have impaired clopidogrel-induced antiplatelet effect. Ticagrelor and prasugrel are two latest generation P2Y. This study, involving 140 patients with T2DM following percutaneous coronary intervention (PCI), evaluated the efficacy of aspirin upon concomitant use of prasugrel (10 mg/d) or ticagrelor (90 mg/d). Platelet reactivity was assessed by value of ADP-induced light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) at baseline, 7 and 30 days after randomized P2Y. Although ticagrelor and prasugrel have similar platelet inhibitory effects in patients with T2DM, if a P2Y

Topics: Adenosine; Aged; Aspirin; Coronary Disease; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor; Time Factors

Lower extremity arterial disease (LEAD) occurs more common in patients with diabetes than without diabetes. Microvascular complications of diabetes contribute to higher rates of adverse limb events in patients with LEAD. Blood flow in the macrocirculation and microcirculation is reduced with increasing low-shear and high-shear blood viscosity. We hypothesize that the adenosine enhancing properties of ticagrelor will reduce low-shear blood viscosity and improve microcirculatory flow in the dorsum of the feet of patients with type 2 diabetes. Ticagrelor is a P2Y12 receptor antagonist with evidence of cardiovascular event reduction in patients with acute coronary syndromes and those with a previous myocardial infarction. In a large multicenter trial of patients with symptomatic LEAD and a history of limb revascularization, ticagrelor was no more effective than clopidogrel in reducing cardiovascular disease events; however, this trial was not designed to investigate microvascular complications of diabetes.. Hema-kinesis will evaluate whether ticagrelor monotherapy or ticagrelor combined with aspirin as compared with aspirin monotherapy can reduce blood viscosity-dependent blood flow in the feet of type 2 diabetes patients with LEAD. Eligible study participants will be randomized into a three-arm double-dummy crossover trial design. All subjects will have baseline blood viscosity measurements and determinations of microvascular flow using laser Doppler flowmetry. If the results of Hema-kinesis are positive, ticagrelor should be considered as treatment to reduce microvascular complications of LEAD in patients with type 2 diabetes.

Topics: Aspirin; Blood Flow Velocity; Blood Viscosity; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Drug Therapy, Combination; Humans; Laser-Doppler Flowmetry; Lower Extremity; Microcirculation; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Regional Blood Flow; Ticagrelor; Time Factors; Treatment Outcome

Diabetes confers an increased risk for atherosclerotic cardiovascular disease, but less is known about the independent risk diabetes confers on major cardiovascular and limb events in patients with symptomatic peripheral artery disease (PAD) on contemporary management.. The authors sought to assess the risk of cardiovascular and limb events in patients with PAD and diabetes as compared with those with PAD alone.. In the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial, 13,885 patients with symptomatic PAD were evaluated with a primary endpoint of an adjudicated composite of major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, ischemic stroke) followed over a median of ∼30 months. The diabetes subgroup was analyzed compared with the subgroup without diabetes, and further examined for diabetes-specific factors such as glycosylated hemoglobin (HbA. A total of 5,345 patients (38.5%) had diabetes; the majority (n = 5,134 [96.1%]) had type 2 diabetes. The primary endpoint occurred in 15.9% of patients with PAD and diabetes as compared with 10.4% of those without diabetes (absolute risk difference 5.5%; adjusted hazard ratio: 1.56; 95% confidence interval [CI]: 1.41 to 1.72; p < 0.001). Every 1% increase in HbA. Patients with PAD and diabetes are at high risk for cardiovascular and limb ischemic events, even on contemporary therapies. Every 1% increase in HbA

Topics: Aged; Diabetes Mellitus, Type 2; Female; Humans; Ischemia; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Ticagrelor; Treatment Outcome

In diabetic patients a predisposed coronary microcirculation along with a higher risk of distal particulate embolization during primary percutaneous intervention (PCI) increases the risk of peri-procedural microcirculatory damage. However, new antiplatelet agents, in particular Ticagrelor, may protect the microcirculation through its adenosine-mediated vasodilatory effects.. PREDICT is an original, prospective, randomized, multicenter controlled study designed to investigate the protective effect of Ticagrelor on the microcirculation during PCI in patient with diabetes mellitus type 2 or pre-diabetic status. The primary endpoints of this study aim to test (i) the decrease in microcirculatory resistance with antiplatelet therapy (Ticagrelor > Clopidogrel; mechanistic effect) and (ii) the relative microcirculatory protection of Ticagrelor compared to Clopidogrel during PCI (Ticagrelor < Clopidogrel; protective effect).. PREDICT will be the first multicentre clinical trial to test the adenosine-mediated vasodilatory effect of Ticagrelor on the microcirculation during PCI in diabetic patients. The results will provide important insights into the prospective beneficial effect of this drug in preventing microvascular impairment related to PCI ( http://www.clinicaltrials.gov No. NCT02698618).

Topics: Adenosine; Blood Platelets; Clinical Protocols; Clopidogrel; Coronary Artery Disease; Coronary Circulation; Diabetes Mellitus, Type 2; Humans; Microcirculation; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Research Design; Risk Factors; Spain; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome; Vasodilation

Trimetazidine (TMZ) improves clinical outcomes in patients with chronic heart failure and stable coronary artery disease. No study has yet evaluated the efficacy of TMZ in type 2 diabetes patients with acute myocardial infarction (AMI) undergoing Percutaneous Coronary Intervention (PCI). We performed this study to evaluate the efficacy TMZ in DM patients with AMI undergoing PCI, such as the effect on reductions in myocardial enzyme, improvements in liver function, modulation of glucose levels, and improvement in cardiac function.. For this randomized study, we enrolled 173 AMI patients with type 2 diabetes undergoing PCI between January 1, 2014, and January 1, 2016. All patients received aspirin and ticagrelor upon admission and throughout their hospitalization. Patients in the experimental group were treated with a loading dose of 60mg TMZ at admission, and 20 mg TMZ three times a day thereafter. 89 patients were included in experimental group, and 84 patients were included in control group. All patients received PCI treatments. The endpoints evaluated were serum creatine kinase and its isoenzyme (CK and CK-MB), cardiac troponin I (cTNI), serum creatinine (Cr), serum urea, blood glucose, serum glutamic pyruvic transaminase (ALT), serum glutamic oxaloacetictransaminase (AST), left atrial dimension (LA), left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), and cardiac output (CO).. Compared with the control group, TMZ treatment significantly reduced CK and CK-MB on the second day in hospital ([797±582] vs. [1092±1114]; [80±60] vs. [105±100]; p=0.029, p=0.041, respectively), and cTNI after one and six days in hospital ([13.5±12.7] vs. [19.8±19.2]; [3.3±3.2] vs. [4.8±4.7]; two-tailed p=0.012). In addition, TMZ significantly lowered liver enzymes (ALT, AST) at 6days ([29.0±11.6] vs. [42.4±24.5]; [39.8±17.3] vs. [69.2±70.0]; two-tailed p=0.000), lowered glucose after 6days ([6.80±2.12] vs. [7.59±2.24]; p=0.019), and increased LVEF after ten to fourteen days ([58.4±8.6] vs. [54.9±8.4]; p=0.008). There were no significant effect on Cr and serum urea (p=0.988, p=0.569, respectively), nor on LA, LVEDD, and CO ([36.3±4.5] vs. [37.0±4.1], p=0.264; [52.0±4.9] vs. [53.1±4.6], p=0.128; [5.4±0.9] vs. [5.4±0.9], p=0.929, respectively).. Among type 2 diabetic patients with AMI undergoing PCI, TMZ significantly reduces serum myocardial enzyme, improves liver function, adjusts blood glucose and improves cardiac function.

Topics: Adenosine; Aged; Alanine Transaminase; Aspartate Aminotransferases; Aspirin; Blood Glucose; Cardiac Output; China; Creatine Kinase; Creatine Kinase, MB Form; Creatinine; Diabetes Mellitus, Type 2; Echocardiography; Female; Glycated Hemoglobin; Heart Atria; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Stroke Volume; Ticagrelor; Treatment Outcome; Trimetazidine; Troponin I; Urea; Vasodilator Agents

Type-2 Diabetes Mellitus [T2DM] is associated with increased platelet reactivity and hypo-response to antiplatelet drugs. Ticagrelor, with its faster and more potent antiplatelet effects, was shown to reduce adverse events more than clopidogrel in the overall CAD patient population of PLATO trial, but the benefits did not reach statistical significance in the T2DM subgroup. To better understand these findings, we compared the antithrombotic effects of ticagrelor versus with clopidogrel in T2DM patients with cardiovascular disease. In a randomized, 2 treatment-sequence, crossover-design, T2DM patients (n=20, 57±8 years, 60 % male) received a loading-dose [LD] plus one week of daily-therapy [DT] of clopidogrel or ticagrelor. Treatment effects were assessed by measuring thrombus formation (Badimon Chamber) and platelet aggregation (Multiple Electrode Aggregometry (MEA) Analyzer and VerifyNow®) at 2- and 6-hour post-LD and on Day-7 of DT, in comparison with pre-treatment baseline. After 2 weeks of washout, patients switched to the second treatment under identical testing conditions. Ticagrelor significantly reduced thrombus formation versus baseline at 2- and 6-hour post-LD and Day-7 of DT (33 %, 40 % and 31 %, respectively, p<0.01 for all) whereas thrombus reductions with clopidogrel were much lower and significant only at 6-hour post-LD (16 %, 20 % and 17 %, respectively). Antithrombotic effect of ticagrelor at 6-hour was significantly stronger than clopidogrel (p<0.05). Platelet aggregation (MEA and VerifyNow®) was inhibited by both treatments but effects of ticagrelor were significantly stronger at each time-point. Ticagrelor exhibits a faster and more potent antithrombotic effect than clopidogrel in T2DM patients with cardiovascular disease, supporting its use in this population.

Topics: Adenosine; Aged; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Coronary Thrombosis; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Function Tests; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome

This study compared adenosine-associated pleiotropic effects of the 2 P2Y. Both ticagrelor and prasugrel have potent antiplatelet effects. However, only ticagrelor inhibits cellular uptake of adenosine.. Using a randomized, crossover design with 10-week follow-up ticagrelor or prasugrel was administered to type 2 diabetic patients with non-ST-segment elevation acute coronary syndrome requiring stent implantation. A total of 62 patients underwent randomization in a 1:1 ratio to receive ticagrelor or prasugrel for 5 weeks followed by a direct cross over to the alternative treatment for 5 additional weeks. Brachial artery flow-mediated dilation, inflammatory markers, and number of circulating EPCs were compared.. Improvement in brachial artery flow-mediated dilation was greater in the ticagrelor group (0.15 ± 0.19 mm vs. -0.03 ± 0.18 mm; p < 0.001). Moreover, ticagrelor compared with prasugrel decreased interleukin 6 (-0.58 ± 0.43 pg/ml vs. -0.05 ± 0.24 pg/ml; p < 0.001), tumor necrosis factor alpha (-5.62 ± 4.40 pg/ml vs. -0.42 ± 2.64 pg/ml; p < 0.001), and increased adiponectin (2.31 ± 2.00 μg/ml vs. 0.08 ± 1.50 μg/ml; p < 0.001) during 10-week follow-up. Other inflammatory cytokines like high-sensitivity C-reactive protein and soluble vascular cell adhesion molecule-1 were decreased in both groups. Ticagrelor compared with prasugrel significantly increased absolute numbers of circulating EPCs CD34+/KDR+ (42.5 ± 37.8 per μl vs. -28.2 ± 23.7 per μl; p < 0.001), CD34+/CD117+ (51.9 ± 77.2 per μl vs. -66.3 ± 45.2 per μl; p < 0.001), and CD34+/CD133+ (55.2 ± 69.2 per μl vs. -28.0 ± 34.1 per μl; p < 0.001).. Compared with prasugrel, ticagrelor significantly decreased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha and increased circulating EPCs, contributing to improved arterial endothelial function in diabetic non-ST-segment elevation acute coronary syndrome patients. Thus, data support that pleiotropic effects of ticagrelor beyond its potent antiplatelet effects could contribute to additional clinical benefits. (Comparison of Ticagrelor vs. Prasugrel on Inflammation, Arterial Stiffness, Endothelial Function, and Circulating Endothelial Progenitor Cells in Diabetic Patients With Non-ST Elevation Acute Coronary Syndrome [NSTE-ACS] Requiring Coronary Stenting; NCT02487732).

Topics: Acute Coronary Syndrome; Adenosine; Adult; Aged; Anti-Inflammatory Agents; Biomarkers; Brachial Artery; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelial Progenitor Cells; Female; Humans; Inflammation Mediators; Male; Middle Aged; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Seoul; Stents; Ticagrelor; Time Factors; Treatment Outcome; Vasodilation

Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic profiles of these drugs in DM patients remains poorly explored and represented the aim of this study.. In this prospective, randomized, double-blind, double-dummy, crossover pharmacodynamic study, aspirin-treated DM patients (n=50) with coronary artery disease were randomly assigned to receive prasugrel (60 mg loading dose [LD]/10 mg maintenance dose once daily) or ticagrelor (180 mg LD/90 mg maintenance dose twice daily) for 1 week. Pharmacodynamic assessments were conducted using 4 different assays, including VerifyNow P2Y12, vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate, which allowed us to explore ADP- and non-ADP-induced (arachidonic acid-, collagen-, thrombin receptor-activating, peptide-induced) platelet signaling pathways. The acute (baseline, 30 minutes, and 2 hours post-LD) and maintenance (1 week) effects of therapy were assessed. The primary end point of the study was the comparison of P2Y12 reaction units determined by VerifyNow P2Y12 at 1 week between prasugrel and ticagrelor.. ADP- and non-ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and maintenance dose. P2Y12 reaction units defined by VerifyNow were similar between prasugrel and ticagrelor at 30 minutes and 2 hours post-LD. At 1 week, P2Y12 reaction units were significantly lower with ticagrelor than with prasugrel (52 [32-72] versus 83 [63-103]; least-square means difference: -31; 95% confidence interval, -57 to -4; P=0.022; primary end point). Pharmacodynamic assessments measured by vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1 week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points.. In DM patients with coronary artery disease, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity in comparison with prasugrel in the acute and chronic phases of treatment, whereas the inhibition of measures of non-ADP-induced platelet reactivity was not significantly different between the 2 agents.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01852214.

Topics: Adenosine; Adolescent; Adult; Aged; Coronary Artery Disease; Cross-Over Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Ticagrelor

Topics: Adenosine; Clopidogrel; Coronary Artery Disease; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Ticagrelor; Ticlopidine

It has been postulated that prasugrel might be the preferred treatment option in diabetes mellitus (DM) patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel.. In a prospective, single-center, single-blind, crossover study, 30 consecutive ACS patients with DM who had been pretreated with clopidogrel were randomized to either 90 mg ticagrelor twice daily or 10 mg prasugrel once daily with a 15-day treatment period. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay, measured in P2Y12 reaction units (PRU).. PR was significantly lower after ticagrelor (45.2 PRU [95% CI 27.4-63.1]) compared with prasugrel (80.8 PRU [63.0-98.7]), with a least squares mean difference of -35.6 PRU (-55.2 to -15.9, P = 0.001). High PR rate was 0% for ticagrelor and 3.3% for prasugrel (P = 1.0).. In DM patients with ACS who had been pretreated with clopidogrel and who undergo PCI, ticagrelor achieves a significantly higher platelet inhibition than prasugrel. Both antiplatelet agents effectively treat high PR. The relevance of these findings to the clinical efficacy and safety of ticagrelor and prasugrel in DM patients needs further elucidation.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Clopidogrel; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Piperazines; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Single-Blind Method; Thiophenes; Ticagrelor; Ticlopidine

patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control.. we analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76-1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66-1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36-1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81-1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70-0.91; HR: 0.78, 95% CI: 0.65-0.93; and HR: 0.62, 95% CI: 0.39-1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86-1.12).. ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Blood Glucose; Clopidogrel; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Ticagrelor; Ticlopidine; Treatment Outcome

Topics: Acute Coronary Syndrome; Clopidogrel; Diabetes Mellitus, Type 2; Hemorrhage; Hospitals; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Ticagrelor; Treatment Outcome

We compared P2Y. Overall, there were no differences of P2Y. Prasugrel and ticagrelor inhibit P2Y

Topics: Acute Coronary Syndrome; Adenosine; Diabetes Mellitus, Type 2; Humans; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Proteinase-Activated; Ticagrelor

Patients with type-2 diabetes are twice as likely to suffer from acute myocardial infarction (AMI) and have a higher incidence of recurrent events than their non-diabetic counterparts. Ticagrelor is a platelet inhibitor known to reduce major adverse cardiovascular events (MACE) in AMI patients. This study measures the level and change in platelet activation and aggregation at the time of and following an AMI in patients with and without diabetes treated with ticagrelor.. Ninety-seven patients were prospectively enrolled (diabetes, N = 33; no diabetes, N = 64). No difference was observed in the expression of P-selectin and PAC-1 at any given point between diabetes and non-diabetes groups (p > 0.05). No difference was observed in the percentage of platelet bound to leukocytes at any measured timepoint between patients with and without diabetes (p > 0.05). Platelet leukocyte aggregation was suppressed during the acute phase compared to quiescence equally among both groups.. Ticagrelor demonstrated similar in-vivo effects on platelet activation and aggregation regardless of diabetes status in patients presenting with AMI.

Topics: Diabetes Mellitus, Type 2; Humans; Myocardial Infarction; P-Selectin; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Ticagrelor; Treatment Outcome

Pleiotropic effects have been implicated in clinical benefits of ticagrelor compared to thienopyridine P2Y. Biochemical indices of endothelial dysfunction/activation and platelet reactivity by multiple electrode aggregometry were compared in 126 stable post-ACS subjects (mean age: 65 ± 10 years, 92 men and 34 women), including patients with (n = 61) or without (n = 65) coexistent type 2 diabetes (T2DM) on uneventful maintenance DAPT with either ticagrelor (90 mg b.d.) or clopidogrel (75 mg o.d.) in addition to low-dose aspirin. Exclusion criteria included a complicated in-hospital course, symptomatic heart failure, left ventricular ejection fraction < 40% and relevant coexistent diseases except for well-controlled diabetes, mild renal insufficiency or hypertension.. Clinical characteristics were similar in patients on ticagrelor (n = 62) and clopidogrel (n = 64). The adenosine diphosphate-induced platelet aggregation and circulating soluble P-selectin (sP-selectin) were decreased in ticagrelor users irrespective of T2DM status (p < 0.001 and p < 0.01 for platelet reactivity and sP-selectin, respectively). Plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were lower in T2DM subjects on ticagrelor vs. clopidogrel (758 ± 162 vs. 913 ± 217 µg/L, p < 0.01). In contrast, plasma sVCAM-1 was similar in non-diabetic patients on ticagrelor and clopidogrel (872 ± 203 vs. 821 ± 210 µg/L, p > 0.7). The concentrations of sE-selectin, monocyte chemoattractant protein-1 and asymmetric dimethylarginine did not differ according to the type of P2Y. Our preliminary findings may suggest an association of ticagrelor-based maintenance DAPT with favorable endothelial effects compared to clopidogrel users in stable post-ACS patients with T2DM. If proven, this could contribute to more pronounced clinical benefits of ticagrelor in diabetic subjects.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Clopidogrel; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Stroke Volume; Ticagrelor; Ventricular Function, Left

Ticagrelor and dapagliflozin can suppress the activation of the NOD-like receptor 3 (NLRP3)-inflammasome and activate AMP-activated protein kinase (AMPK). The anti-inflammatory effects of dapagliflozin has been shown to depend on AMPK activation. Dapagliflozin and ticagrelor have been shown to have additive effects on the progression of diabetic cardiomyopathy in BTBR ob/ob mice with type-2 diabetes. We assessed whether dapagliflozin and ticagrelor have additive effects on the activation of the NLRP3-inflammasome and the progression of diabetic nephropathy in mice with type-2 diabetes.. Eight-week-old BTBR received either no-drug, dapagliflozin (1.5 mg/kg/d), ticagrelor (100 mg/kg/d), or their combination for 12 weeks. Blood was assessed weekly for glucose and urine for glucose and albumin. After 12 weeks, blood creatinine, cystatin C, inflammasome activation, and insulin were assessed by ELISA. Renal cortex samples were assessed by hematoxylin and eosin and periodic acid-Schiff staining. RT-PCR and immunoblotting were used to evaluate fibrosis and the activation of Akt, AMPK and the inflammasome.. Both ticagrelor and dapagliflozin reduced serum creatinine and cystatin C levels and urinary albumin. Both drugs attenuated the increase in glomerular area and mesangial matrix index. Both drugs decreased collagen-1 and collagen-3 expression and the activation of the NLRP3-inflammasome. Both drugs increased P-AMPK levels, but only dapagliflozin increased P-Akt levels. Overall, the protective effects of dapagliflozin and ticagrelor were additive.. Dapagliflozin and ticagrelor attenuated the progression of diabetic nephropathy in BTBR ob/ob mice with additive effects of the combination. This was associated with AMPK activation and reduced activation of the NLRP3 inflammasome, whereas only dapagliflozin increased Akt activation.

Topics: Albumins; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Benzhydryl Compounds; Creatinine; Cystatin C; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eosine Yellowish-(YS); Glucose; Glucosides; Hematoxylin; Inflammasomes; Insulins; Kidney; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Periodic Acid; Proto-Oncogene Proteins c-akt; Ticagrelor

Topics: Aspirin; Coronary Artery Disease; Diabetes Mellitus, Type 2; Hemorrhage; Humans; Ticagrelor

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Humans; Male; Randomized Controlled Trials as Topic; Ticagrelor; Treatment Outcome

Ticagrelor, a P2Y12 receptor antagonist, and dapagliflozin, a sodium-glucose-cotransporter-2 inhibitor, suppress the activation of the NLRP3 inflammasome. The anti-inflammatory effects of dapagliflozin depend on AMPK activation. Also, ticagrelor can activate AMPK. We assessed whether dapagliflozin and ticagrelor have additive effects in attenuating the progression of diabetic cardiomyopathy in T2DM mice.. Eight-week-old BTBR and wild-type mice received no drug, dapagliflozin (1.5 mg/kg/day), ticagrelor (100 mg/kg/day), or their combination for 12 weeks. Heart function was evaluated by echocardiography and heart tissue samples were assessed for fibrosis, apoptosis, qRT-PCR, and immunoblotting.. Both drugs attenuated the progression of diabetic cardiomyopathy as evident by improvements in left ventricular end-systolic and end-diastolic volumes and left ventricular ejection fraction, which were further improved by the combination. Both drugs attenuated the activation of the NOD-like receptor 3 (NLRP3) inflammasome and fibrosis. The effect of the combination was significantly greater than each drug alone on myocardial tissue necrotic factorα (TNFα) and interleukin-6 (IL-6) levels, suggesting additive effects. The combination had also a greater effect on ASC, collagen-1, and collagen-3 mRNA levels than each drug alone. While both drugs activated adenosine mono-phosphate kinase (AMPK), only dapagliflozin activated mTOR and increased RICTOR levels. Moreover, only dapagliflozin decreased myocardial BNP and Caspase-1 mRNA levels, and the effects of dapagliflozin on NLRP3 and collagen-3 mRNA levels were significantly greater than those of ticagrelor.. Both dapagliflozin and ticagrelor attenuated the progression of diabetic cardiomyopathy, the activation of the NLRP3 inflammasome, and fibrosis in BTBR mice with additive effects of the combination. While both dapagliflozin and ticagrelor activated AMPK, only dapagliflozin activated mTOR complex 2 (mTORC2) in hearts of BTBR mice.

Topics: AMP-Activated Protein Kinases; Animals; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Disease Progression; Enzyme Activation; Fibrosis; Glucosides; Inflammasomes; Male; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred C57BL; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Purinergic P2Y Receptor Antagonists; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Ticagrelor; TOR Serine-Threonine Kinases; Ventricular Function, Left; Ventricular Remodeling

Topics: Aged; Coronary Artery Disease; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Ticagrelor; Treatment Outcome

Topics: Coronary Artery Disease; Diabetes Mellitus, Type 2; Humans; Platelet Aggregation Inhibitors; Ticagrelor; Ticlopidine

Central adjudication in randomised controlled outcome-driven trials represents a traditional approach to maintain data integrity by applying uniformed rules for assessment of clinical events. It was the purpose of this investigation to determine the patterns of myocardial infarction (MI) adjudication in the TRITON, RECORD, and PLATO trials. We were matching centrally-adjudicated MI's (CAMI's) from the official trial publication with the site-reported MI (SRMI's) count from the Food and Drug Administration's secondary analyses for the investigational compounds prasugrel (TRITON), rosiglitazone (RECORD), and ticagrelor (PLATO). CAMI numbers showed a remarkable discrepancy to SRMI's by more than a doubling of the difference: from 72 to 145 events in TRITON favoring prasugrel (from a hazard ratio [HR]=0.76, p=0.08; to a HR=0.76, p<0.001), and from 44 to 89 events in favour of ticagrelor in PLATO (from a HR=0.94, p=0.095; to a HR=0.84, p<0.001). In contrast, in the RECORD trial, the CAMI count was less than the SRMI count (from 24 to 8 events, from a HR=1.42, p=0.93; to a HR=1.14, p=0.96), in this case diminishing cardiovascular hazards in favour of rosiglitazone. In conclusion, central adjudication in the TRITON, the RECORD, and the PLATO trial turned out to have a critical impact on study outcomes. Trial publications should in the future include site-reported major efficacy and safety endpoints to preserve data integrity. The regulatory authorities should consider independent audits when there is a major disagreement between centrally adjudicated and site reported events influencing the results of a major clinical trial.

Topics: Acute Coronary Syndrome; Adenosine; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Judgment; Metformin; Multicenter Studies as Topic; Myocardial Infarction; Observer Variation; Outcome Assessment, Health Care; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Process Assessment, Health Care; Randomized Controlled Trials as Topic; Rosiglitazone; Stroke; Sulfonylurea Compounds; Thiazolidinediones; Thiophenes; Ticagrelor