ticagrelor and Peripheral-Arterial-Disease

High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD.. A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group.. Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking.. Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.

Topics: Aspirin; Clopidogrel; Fibrinolytic Agents; Hemorrhage; Humans; Network Meta-Analysis; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Ticagrelor; Vitamin K

Antiplatelet therapy is recommended among patients with established atherosclerosis. We compared monotherapy with a P2Y. In this systematic review and meta-analysis, all randomised trials comparing P2Y. A total of nine randomised trials were identified and included in this study, and 42 108 patients randomly allocated to a P2Y. Compared with aspirin monotherapy, P2Y. Italian Ministry of Education.

Topics: Aged; Aspirin; Atherosclerosis; Cerebrovascular Disorders; Clopidogrel; Coronary Disease; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Secondary Prevention; Stroke; Ticagrelor; Ticlopidine

Ticagrelor is a P2Y

Topics: Animals; Coronary Artery Disease; Endothelium, Vascular; Hemodynamics; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Ticagrelor

Cardiovascular disease (CVD) is the main cause of death in the world. Coronary artery disease (CAD) is the most common form of CVD presentation, but the prevalence of peripheral artery disease (PAD) is increasing. Patients with polyvascular disease comprise a very high-risk population that has been infrequently studied. Areas covered: The authors review the current evidence of the efficacy and safety of ticagrelor in the setting of acute coronary syndrome and stable patients post-MI with and without PAD and summarize its pharmacokinetics, pharmacodynamics, and regulatory issues. Expert opinion: Randomized studies showed that ticagrelor is superior to clopidogrel in patients with acute coronary syndromes, and is superior to placebo in the chronic phase (>1 year) post-myocardial infarction. Sub-analyses of these studies suggest that patients with myocardial infarction and PAD, compared to patients without these characteristics, may have greater benefit with ticagrelor. Nonetheless, the global evidence about the role of ticagrelor in patients with myocardial infarction and PAD remains relatively sparse, and a prospective randomized trial testing this hypothesis would be necessary to provide more definite data regarding the efficacy and safety of ticagrelor in this very high-risk population.

Topics: Acute Coronary Syndrome; Adenosine; Government Regulation; Half-Life; Hemorrhage; Humans; Myocardial Infarction; Peripheral Arterial Disease; Purinergic P2Y Receptor Antagonists; Ticagrelor; Treatment Outcome

Acetylsalicylic acid and clopidogrel are two antiplatelet agents currently used in the therapy of peripheral arterial disease. Cilostazol also inhibits platelet aggegration. These agents present limitations that novel antiplatelet agents may overcome.. The aim of this manuscript is to review current data on the use of novel antiplatelet agents in peripheral arterial disease.. An extensive search in the English medical literature has yielded a number of publications on a number of novel antiplatelet agents; atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel, and prasugrel.. Data on atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel and prasugrel come mainly from cardiology publications. Limitations, side effects and effectiveness of each of these agents are studied, but their use in peripheral arterial disease is limited, especially for those agents that have not still been approved for this indication. As expected, main side effect of most of these agents is haemorrhage, but other important side effects limit the use of some of these agents in specific subgroups of patients.. Novel antiplatelet agents demonstrate a range of promising characteristics, but further study and clinical trials are necessary for them to be considered safe and effective.

Topics: Adenosine; Adenosine Monophosphate; Imines; Lactones; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Quinazolinones; Sulfonamides; Ticagrelor

In the peripheral arteries, a thrombus superimposed on atherosclerosis contributes to the progression of peripheral artery disease (PAD), producing intermittent claudication (IC), ischemic necrosis, and, potentially, loss of the limb. PAD with IC is often undiagnosed and, in turn, undertreated. The low percentage of diagnosis (∼30%) in this setting of PAD is of particular concern because of the potential worsening of PAD (amputation) and the high risk of adverse vascular outcomes (vascular death, coronary artery disease, stroke). A Medline literature search of the highest-quality systematic reviews and meta-analyses of randomized controlled trials documents that, due to risk of bias, imprecision, and indirectness, the overall quality of the evidence concerning diagnostic tools and antithrombotic interventions in PAD is generally low. Areas of research emerge from the information collected. Appropriate treatments for PAD patients will only derive from ad-hoc studies. Innovative imaging techniques are needed to identify PAD subjects at the highest vascular risk. Whether IC unresponsive to physical exercise and smoking cessation identifies those with a heritable predisposition to more severe vascular events deserves to be addressed. Devising ways to improve prevention of vascular events in patients with PAD implies a co-ordinated approach in vascular medicine.

Topics: Adenosine; Aspirin; Asymptomatic Diseases; Cilostazol; Clopidogrel; Fibrinolytic Agents; Humans; Intermittent Claudication; Ischemia; Lower Extremity; Meta-Analysis as Topic; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Primary Prevention; Review Literature as Topic; Secondary Prevention; Stroke; Tetrazoles; Thrombosis; Ticagrelor; Ticlopidine

Peripheral arterial disease (PAD) is a manifestation, and marker of severity, of a generalized atherosclerotic process. Antiplatelet therapy is recommended to prevent cardiovascular events but much of the evidence to support this is drawn from studies on older drugs.. In this review, the authors discuss the available evidence for the basis of current recommendations and review the data from Phase I to III trials on ticagrelor as a potential future treatment. This paper also reviews the properties of ticagrelor, its adverse effects, and how it differs from current recommended antiplatelet agents. As it is also more potent, a personalized approach to antiplatelet therapy may prove useful. It further highlights the additional effects of ticagrelor mediated by adenosine and their potential benefits, which may provide an explanation to its superior outcomes in trials comparing it with clopidogrel.. Although there is a current lack of evidence to support the use of ticagrelor in patients with PAD, its unique pleomorphic properties make it attractive for future investigations and development of similar drugs.

Topics: Adenosine; Animals; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Ticagrelor

Regional variations exist in the epidemiology of peripheral artery disease (PAD), in comorbidities, use of secondary prevention, and outcomes. Large studies of these variations in worldwide populations are rare. The EUCLID (Examining Use of tiCagreLor In peripheral artery Disease) trial included 13,885 patients with PAD from four geographical regions (Central/South America, Europe, Asia, North America) and compared monotherapy with ticagrelor and clopidogrel. Inclusion criteria were either an ankle-brachial index < 0.80 or a prior revascularization. The primary efficacy endpoint was time to first occurrence of any event in the composite of cardiovascular death, myocardial infarction, or ischemic stroke and did not differ between the study arms. This post hoc analysis of EUCLID confirmed that regional differences occurred in the inclusion criteria with more prior revascularization in North America (73.9%) and Asia (72.5%) compared with Central/South America (34.0%) and Europe (51.6%). The characteristics of patients also differed. Prior amputation at baseline was most frequent in Central/South America (6.3%) compared with other regions (1.6-2.8%). A history of stroke was most common in Asia, coronary heart disease in North America, and diabetes in Central/South America compared with other regions. The incidence of outcomes in patients with PAD varied by region. North America had the highest rate of the primary combined endpoint (5.97 events/100 patient-years). Corresponding rates were 4.80, 3.95, and 3.87 for Asia, Europe, and Central/South America, respectively. Hospitalization for acute limb ischemia (events/100 patient-years) was most frequent in Europe (0.75) and North America (0.74) compared with Asia (0.60) and Central/South America (0.33). Adjustment for inclusion criteria and relevant PAD characteristics did not have a major impact on these regional differences. Further adjustment for concomitant disease, risk factors, and preventive medication modified the regional differences only marginally. In conclusion, substantial regional differences were found in cardiovascular and limb outcomes in patients with PAD and were not explained by variation in the category of included patients, concomitant disease, risk factors, and prevention. Such differences, which may be due to variation in other factors such as background population rates or clinical care, need to be considered when designing and interpreting large international studies (

Topics: Clopidogrel; Humans; Internationality; Ischemia; Ischemic Stroke; Myocardial Infarction; Peripheral Arterial Disease; Ticagrelor; Treatment Outcome

Topics: Clopidogrel; Humans; Lower Extremity; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Ticagrelor; Treatment Outcome

Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events.. EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined.. TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and β-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P < .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event.. In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and β-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

Topics: Adrenergic beta-Antagonists; Age Factors; Aged; Cardiovascular Diseases; Clopidogrel; Double-Blind Method; Female; Hemorrhage; Humans; Incidence; Intention to Treat Analysis; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Residence Characteristics; Risk Factors; Ticagrelor; Time Factors

Peripheral artery disease (PAD) is associated with increased risk of mortality, cardiovascular morbidity, and major amputation. Data on major amputation from a large randomized trial that included a substantial cohort of patients without critical limb ischemia (CLI) have not been described. The objective was to describe the incidence and types of amputations in the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) population, subcategorize amputations in the CLI versus no CLI cohorts, and describe the events surrounding major amputation.. Postrandomization major amputation was analyzed in the EUCLID trial. Patients were stratified by baseline CLI status. The occurrence of major amputation was ascertained and defined as the highest level. Perioperative events surrounding major amputation were obtained including acute limb ischemia, revascularization, and all-cause mortality. All variables were assessed for significance in univariable and multivariable models. The rate of major amputation during the course of the trial was 1.6% overall, 8.4% in the CLI at baseline group, and 1.2% in the no CLI at baseline group. The annualized rate of major amputation was 0.6% in PAD overall, 3.9% in the CLI at baseline group, and 0.5% in the no CLI at baseline group. Several factors were associated with increased risk of major amputation, including history of amputation, the presence of diabetes mellitus, baseline Rutherford category 4 to 6, and an ankle-brachial index <0.8. Factors associated with a lower risk for major amputation included prior statin use. The 30-day mortality rate after major amputation was 6.5% overall, 5.6% in the CLI at baseline group, and 6.8% in the no CLI at baseline group. The annual mortality rate following major amputation was 22.8% in the CLI at baseline group and 16.0% in the no CLI at baseline group.. The risk factors for major amputation in EUCLID patients are similar to previous large registries' reports except for diabetes mellitus in patients with CLI. The mortality following major amputation is lower in the EUCLID trial compared with registry data. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

Topics: Aged; Amputation, Surgical; Critical Illness; Female; Humans; Incidence; Ischemia; Limb Salvage; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Ticagrelor; Time Factors; Treatment Outcome

Background There are limited data on health status instruments in patients with peripheral artery disease and cardiovascular and limb events. We evaluated the relationship between health status changes and cardiovascular and limb events. Methods and Results In an analysis of the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) trial, we examined the characteristics of 13 801 patients by tertile of health status instrument scores collected in the trial (EuroQol 5-Dimensions [EQ-5D], EQ visual analog scale [VAS], and peripheral artery questionnaire). We assessed the association between the baseline health status measurements and major adverse cardiovascular events, major adverse limb events, and lower-extremity revascularization procedures during trial follow-up and the association between 12-month health status change scores and subsequent end points during follow-up. There were 13 217 (95%) patients with EQ-5D scores, 13 533 (98%) with VAS scores, and 4431 (32%) with peripheral artery questionnaire scores. Patients in the lowest baseline EQ-5D tertile (0 to <0.69) were more likely to be female with severe claudication compared with the highest tertile (0.79-1.0;

Topics: Cardiovascular Diseases; Double-Blind Method; Female; Health Status Indicators; Humans; Lower Extremity; Male; Middle Aged; Outcome Assessment, Health Care; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Quality of Life; Surveys and Questionnaires; Symptom Assessment; Ticagrelor; Vascular Surgical Procedures; Visual Analog Scale

Patients with peripheral artery disease have a high risk of future cardiovascular disease events and mortality. Little is known about the changes in symptom classification over time in patients with peripheral artery disease and the association of changes in symptom classification with subsequent cardiovascular disease events.. In this analysis of the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease), we examined the changes in Rutherford classification (RC) of patients over 12 months. We examined the baseline characteristics of patients by change in symptom classification at 12 months (improved=decreased RC, no change, or worsened=increased RC), and the association between changes in symptom classification (RC) at 12 months and subsequent cardiovascular disease events.. Among 12 759 patients, 3240 (25%) were classified as improved by RC at 12 months, 8132 (64%) as no change, and 1387 (11%) as worsened. At 12 months, many patients who were asymptomatic or had mild/moderate claudication at enrollment had no change in symptom classification over 12 months (73.7% and 70.9%). Patients who worsened over 12 months were more likely to have comorbidities (diabetes mellitus and prior myocardial infarction) and more events (myocardial infarction, amputation, and major bleeding) by 12 months postrandomization, all. Patients with comorbidities and prior history of cardiovascular disease events at baseline and within the first 12 months of the trial were more likely to have worsened symptom classification at 12 months. Worsening symptom classification over 12 months was associated subsequently with an increased risk of all-cause death, amputation, and a composite of cardiovascular death, myocardial infarction, or stroke. Graphic Abstract: A graphic abstract is available for this article.

Topics: Aged; Amputation, Surgical; Cardiovascular Diseases; Clopidogrel; Comorbidity; Disease Progression; Female; Humans; Limb Salvage; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prognosis; Risk Assessment; Risk Factors; Symptom Assessment; Ticagrelor; Treatment Outcome

The relationship between invasive vascular procedures and bleeding in patients with peripheral artery disease has not been well described in the literature. This post hoc analysis from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) aimed to describe the incidence of major and minor postprocedural bleeding and characterize the timing and severity of bleeding events relative to the procedure.. EUCLID was a multicenter, randomized controlled trial of 13 885 patients with symptomatic peripheral artery disease that tested the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events. A total of 2661 patients underwent 3062 coronary revascularization, peripheral revascularization, and amputation during the study. The primary safety end point was Thrombolysis in Myocardial Infarction major or minor bleeding. All bleeding events were formally adjudicated by a clinical end point classification group.. Major bleeding events most often occurred ≤7 days following the procedure. The incidence of Thrombolysis in Myocardial Infarction major or minor bleeding ≤7 days following peripheral revascularization (3.3%; 95% CI, 2.5%-4.1%) was similar to rates after coronary revascularization (4.0%; 95% CI, 2.6%-5.4%) and lower extremity amputation (2.3%; 95% CI, 0.8%-3.8%). The severity of bleeding events (as graded by drop in hemoglobin, need for transfusion, bleeding in a critical location, and fatal bleeding) was also similar following peripheral, coronary revascularization, and lower extremity amputation.. The incidence of Thrombolysis in Myocardial Infarction major/minor bleeding following peripheral revascularization is comparable to rates after coronary revascularization and lower extremity amputation, and the majority of bleeding events occur within 7 days following the procedure. The severity of periprocedural bleeding is also similar after procedures, with the most frequently adjudicated reason being a drop in hemoglobin ≥2 g/dL. Future studies should be performed to enhance our understanding of bleeding risk related to revascularization and amputation procedures in peripheral artery disease patients.

Topics: Aged; Amputation, Surgical; Clopidogrel; Double-Blind Method; Endovascular Procedures; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Revascularization; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Risk Factors; Ticagrelor; Time Factors; Treatment Outcome

Patients with peripheral artery disease (PAD) are at high risk for myocardial infarction (MI).. To characterize the incidence and types of MI in a PAD population, identify factors associated with MI, and determine the association of MI with cardiovascular mortality and acute limb ischemia.. The Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) was a double-blind randomized clinical trial conducted at 811 sites in 28 countries that randomized 13 885 patients with symptomatic PAD to monotherapy with ticagrelor or clopidogrel. Participants had an ankle-brachial index (ABI) of 0.80 or less or previous lower extremity revascularization. Median follow-up was 30 months. For these analyses, patients were evaluated for MI occurrence during follow-up irrespective of treatment. Data were analyzed from June 2017 to September 2018.. An adjudication clinical events committee classified MI as type 1 (spontaneous), type 2 (secondary), type 3 (sudden cardiac death), type 4a (less than 48 hours after percutaneous coronary intervention), type 4b (definite stent thrombosis), or type 5 (less than 72 hours after coronary artery bypass graft). A multivariate regression model was developed by stepwise selection to identify factors associated with MI, and a time-dependent multivariate Cox regression analysis was performed to determine the association of MI with cardiovascular death and acute limb ischemia requiring hospitalization.. Of the 13 885 patients included in this analysis, 9997 (72.0%) were male, and the median (interquartile range) age was 66 (60-73) years. Myocardial infarction occurred in 683 patients (4.9%; 2.4 events per 100 patient-years) during a median follow-up of 30 months. Patients experiencing MI were older (median [interquartile range] age, 69 [62-75] vs 66 [60-72] years), more likely to have diabetes (349 of 683 [51.1%] vs 4996 of 13 202 [37.8%]) or a previous lower extremity revascularization (466 of 683 [68.2%] vs 7409 of 13 202 [56.1%]), and had a lower ABI (if included by ABI) compared with censored patients. Of the 683 patients with MI during follow-up, the most common MI type was type 1 (405 [59.3%]), followed by type 2 (236 [34.6%]), type 4a (14 [2.0%]), type 3 (12 [1.8%]), type 4b (11 [1.6%]), and type 5 (5 [0.7%]). Postrandomization MI was independently associated with cardiovascular death (adjusted hazard ratio, 9.0; 95% CI, 7.3-11.2; P < .001) and acute limb ischemia requiring hospitalization (adjusted hazard ratio, 2.5; 95% CI, 1.3-5.0; P = .008).. Approximately 5% of patients with symptomatic PAD had an MI during a median follow-up of 30 months. Type 1 MI (spontaneous) was the most common MI type; however, one-third of MIs were type 2 MI (secondary). More research is needed to identify therapies to reduce the risk of MI in patients with PAD and to improve management of type 2 MI.. ClinicalTrials.gov Identifier: NCT01732822.

Topics: Aged; Ankle Brachial Index; Clopidogrel; Coronary Artery Bypass; Death; Extremities; Female; Hospitalization; Humans; Incidence; Ischemia; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Risk Factors; Ticagrelor

Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registr

Topics: Aged; Clopidogrel; Double-Blind Method; Female; Humans; Intracranial Hemorrhages; Ischemic Attack, Transient; Male; Middle Aged; Peripheral Arterial Disease; Stroke; Ticagrelor

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

Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated.. EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized patients with peripheral artery disease to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index ≤0.80 or previous lower extremity revascularization. Patients were grouped according to the primary outcome, postrandomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were developed for secondary outcomes of major adverse cardiovascular events (myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation.. Among 13 885 patients, 1.7% (n=232) had 293 ALI hospitalizations (0.8 per 100 patient-years). Patients with versus without ALI were younger and more often had previous peripheral revascularization and lower baseline ankle-brachial index. Treatment during ALI hospitalization included endovascular revascularization (39.2%, n=115), surgical bypass (24.6%, n=72), and major amputation (13.0%, n=38). After multivariable adjustment, any previous peripheral revascularization (Hazard Ratio [HR] 4.7, 95% CI 3.3-6.8, P<0.01), baseline atrial fibrillation (HR 1.8, 95% CI 1.1-3.2, P=0.03), and baseline ankle-brachial index ≤0.60 (HR 1.3 per 0.10 decrease, 95% CI 1.1-1.5, P<0.01) were associated with higher ALI risk. Older age (HR 0.8 per 10-year increase, 95% CI 0.7-1.0, P=0.02) and baseline statin use (HR 0.7, 95% CI 0.5-0.9, P<0.01) were associated with lower risk for ALI. There was no relationship between randomized treatment to ticagrelor or clopidogrel and ALI. Among patients with previous revascularization, surgical versus endovascular procedures performed more than 6 months prior were associated with ALI (adjusted HR 2.63, 95% CI 1.75-3.96). In the overall population, ALI hospitalization was associated with subsequent MACE (adjusted HR 1.4, 95% CI 1.0-2.1, P=0.04), all-cause mortality (adjusted HR 3.3, 95% CI 2.4-4.6, P<0.01), and major amputation (adjusted HR 34.2, 95% CI 9.7-20.8, P<0.01).. Previous peripheral revascularization, baseline atrial fibrillation, and lower ankle-brachial index identify peripheral artery disease patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01732822.

Topics: Acute Disease; Aged; Double-Blind Method; Female; Hospitalization; Humans; Ischemia; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Ticagrelor

Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established.. The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss.. In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI.. Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822.

Topics: Adenosine; Aged; Clopidogrel; Female; Hospitalization; Humans; Hypertension; Incidence; Ischemia; Kaplan-Meier Estimate; Limb Salvage; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Proportional Hazards Models; Prospective Studies; Purinergic P2Y Receptor Antagonists; Risk Factors; Stroke; Ticagrelor; Ticlopidine; Treatment Outcome; Vascular Surgical Procedures

There is limited evidence to guide clinical decision-making for antiplatelet therapy in peripheral artery disease (PAD) in the setting of lower extremity endovascular treatment. The Ticagrelor in Peripheral Artery Disease Endovascular Revascularization Study (TI-PAD) evaluated the role of ticagrelor versus aspirin as monotherapy in the management of patients following lower extremity endovascular revascularization. The trial failed to recruit the targeted number of patients, likely due to aspects of the design including the lack of option for dual antiplatelet therapy, and inability to identify suitable patients at study sites. In response, the protocol underwent amendments, but these changes did not adequately stimulate recruitment, and thus TI-PAD was prematurely terminated. This article describes the rationale for TI-PAD and challenges in trial design, subject recruitment and trial operations to better inform the conduct of future trials in PAD revascularization. ClinicalTrials.gov Identifier: NCT02227368.

Topics: Aged; Aspirin; Double-Blind Method; Early Termination of Clinical Trials; Endovascular Procedures; Female; Humans; Lower Extremity; Male; Middle Aged; Patient Selection; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Sample Size; Ticagrelor; Treatment Outcome; United States

Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular morbidity and mortality. We sought to evaluate the risk of concomitant coronary artery disease (CAD) in patients with symptomatic PAD versus PAD without diagnosed CAD, and whether ticagrelor was superior to clopidogrel in reducing that risk. The EUCLID trial randomized 13,885 patients with PAD to antithrombotic monotherapy with ticagrelor or clopidogrel. CAD was defined as prior myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) surgery. Median follow-up was 30 months. Among 4032 (29%) patients with PAD and CAD, 63% had prior MI, 54% prior PCI, and 38% prior CABG. After adjustment for baseline characteristics, patients with PAD and CAD had significantly higher rates of the primary endpoint (cardiovascular death/MI/stroke, 15.3% vs 8.9%, hazard ratio (HR) 1.50, 95% CI: 1.13-1.99; p=0.005), but no statistically significant increase in acute limb ischemia (HR 1.28, 95% CI: 0.57-2.85; p=0.55) or major bleeding (HR 1.10, 95% CI: 0.49-2.48; p=0.81) versus PAD without CAD. Among patients with PAD and CAD, there was no differential treatment effect between ticagrelor versus clopidogrel for the primary efficacy endpoint (HR 1.02, 95% CI: 0.87-1.19; p=0.84), acute limb ischemia (HR 1.03, 95% CI: 0.63-1.69; p=0.89), or major bleeding (HR 1.06, 95% CI: 0.66-1.69; p=0.81). There was a statistically significant interaction between prior coronary stent placement and study treatment ( p=0.03) with a numerical reduction in the primary efficacy endpoint with ticagrelor versus clopidogrel (13.8% vs 16.8%, HR 0.82, 95% CI: 0.65-1.03; p=0.09). Patients with PAD and prior CAD had higher composite rates of cardiovascular death, MI, and ischemic stroke versus PAD without diagnosed CAD. There were no significant differences between ticagrelor and clopidogrel in cardiovascular events or major bleeding. ClinicalTrials.gov Identifier: NCT01732822.

Topics: Aged; Clopidogrel; Coronary Artery Bypass; Coronary Artery Disease; Double-Blind Method; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prospective Studies; Risk Factors; Stents; Stroke; Ticagrelor; Time Factors; Treatment Outcome

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 patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown.. The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding.. Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88-1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86-1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78-1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83-1.59; P=0.41). The median duration of follow-up was ≈30 months.. After adjustment for baseline characteristics, patients enrolled based on previous revascularization for peripheral artery disease had higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, myocardial infarction, and stroke when compared with patients enrolled based on the ankle-brachial index criterion. No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01732822.

Topics: Adenosine; Aged; Clopidogrel; Female; Humans; Lower Extremity; Male; Peripheral Arterial Disease; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine; Treatment Outcome

Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease.. In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months.. The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49).. In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

Topics: Adenosine; Aged; Cardiovascular Diseases; Clopidogrel; Double-Blind Method; Female; Hemorrhage; Humans; Intermittent Claudication; Ischemia; Kaplan-Meier Estimate; Leg; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine

Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI).. This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI.. PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up.. A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663; 19.3% vs. 8.4%; p < 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval: 0.44 to 0.95; p = 0.026).. Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54]; NCT01225562).

Topics: Adenosine; Aged; Aspirin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hemorrhage; Humans; Ischemia; Lower Extremity; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Secondary Prevention; Stroke; Ticagrelor; Vascular Grafting

Topics: Acute Coronary Syndrome; Adenosine; Aged; Arteries; Aspirin; Biomarkers; Clopidogrel; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Extremities; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peripheral Arterial Disease; Prospective Studies; Severity of Illness Index; Survival Rate; Ticagrelor; Ticlopidine; Treatment Outcome

Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events.. EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur.. The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

Topics: Adenosine; Aged; Ankle Brachial Index; Clopidogrel; Disease Progression; Female; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Stroke; Ticagrelor; Ticlopidine; Treatment Outcome

To determine the effect of ticagrelor compared to clopidogrel in patients with peripheral artery disease (PAD) and acute coronary syndromes (ACS).. PLATO (n = 18,624) was a multicentre, double-blind, randomized trial in ACS, that showed a 16% reduction in cardiovascular death (CV-death), myocardial infarction (MI) and stroke with ticagrelor compared with clopidogrel, without significant increase in overall major bleeding. We performed a post-hoc analysis of cardiovascular and bleeding outcomes in PLATO according to reported PAD status at baseline. At one year, CV death, MI or stroke occurred in 19.3% of patients with PAD (n = 1144) compared to 10.2% in patients without PAD (p < 0.001). The Kaplan-Meier one year event rate for the primary endpoint of CV death, MI or stroke in PAD patients treated with ticagrelor as compared with clopidogrel, was 18% vs 20.6% (HR: 0.85 95% CI 0.64-1.11; for PAD status by treatment interaction, p = 0.99) and for death from any cause 8.7% vs 11.9%, (HR: 0.74 95% CI 0.50-1.08; interaction p = 0.73). PLATO-defined major bleeding event rates at one year were 14.8% for ticagrelor compared to 17.9% for clopidogrel, (HR: 0.81 95% CI 0.59-1.10; interaction p = 0.09).. PAD patients have a high rate of ischaemic and bleeding events post ACS. The reduction of CV death, MI or stroke with ticagrelor compared with clopidogrel in PAD patients was consistent with the overall trial result although it did not reach statistical significance. Overall major bleeding was similar between the therapies.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Clopidogrel; Double-Blind Method; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Proportional Hazards Models; Risk Factors; Stroke; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome

Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5 years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76 kg, HR, 0.77; 95% CI, 0.64-0.93; <76 kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF.

Topics: Age Factors; Aged; Clopidogrel; Comorbidity; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Ticagrelor; Time Factors; Treatment Outcome

[Figure: see text].

Topics: Ankle Brachial Index; Humans; Lower Extremity; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Risk Assessment; Ticagrelor

Critical limb-threatening ischemia (CLTI) is associated with an increased risk of major adverse limb events and mortality. High on-treatment platelet reactivity (HPR) is associated with an increased risk of ischemic events, while low on-treatment platelet reactivity (LPR) is associated with an increased risk of bleeding. This study investigates the frequency with which patients with CLTI on clopidogrel or ticagrelor achieve a "therapeutic window" (TW) of platelet inhibition.. Data from the "Switch To Ticagrelor in Critical Limb Ischemia Anti-Platelet Study" were assessed retrospectively to determine the incidence of TW of on-treatment platelet reactivity in 50 consecutive patients with CLTI (mean age: 65.2 ± 10.5 years, 54% male). The data included 4 measurements of patients' platelet reactivity using the VerifyNow P2Y12 Assay: baseline and steady state platelet reactivity on clopidogrel 75 mg daily and on ticagrelor 90 mg twice daily.. At baseline, 46% of patients on clopidogrel were within TW of on-treatment platelet reactivity compared to 10% of patients on ticagrelor (. Although ticagrelor has been proposed as an alternative for patients with HPR on clopidogrel, the current study observes an excess of platelet inhibition with ticagrelor in most patients with CLTI at a dose of 90 mg twice daily.

Topics: Aged; Clopidogrel; Critical Illness; Drug Administration Schedule; Drug Monitoring; Female; Humans; Ischemia; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Ticagrelor; Time Factors; Treatment Outcome

Peripheral artery disease is common and associated with high mortality. There are limited data detailing causes of death among patients with peripheral artery disease.. EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) was a randomized clinical trial that assigned patients with peripheral artery disease to clopidogrel or ticagrelor. We describe the causes of death in EUCLID using mortality end points adjudicated through a clinical events classification process. The association between baseline factors and cardiovascular death was evaluated by Cox proportional hazards modeling. The competing risk of noncardiovascular death was assessed by the cumulative incidence function for cardiovascular death and the Fine and Gray method to ascertain the association between baseline characteristics and cardiovascular mortality.. A total of 1263 out of 13 885 (9.1%) patients died (median follow-up: 30 months). There were 706 patients (55.9%) with a cardiovascular cause of death and 522 (41.3%) with a noncardiovascular cause of death. The most common cause of cardiovascular death was sudden cardiac death (20.1%); while myocardial infarction (5.2%) and ischemic stroke (3.2%) were uncommon. The most common causes of noncardiovascular death were malignancies (17.9%) and infections (11.9%). The factor most associated with a higher risk of cardiovascular death was age per 5 year increase (HR, 1.26 [95% CI, 1.20-1.32]). Female sex was associated with a lower risk of cardiovascular death (HR, 0.68 [95% CI, 0.56-0.82]). To evaluate the effect of noncardiovascular death as a competing risk, we superimposed the cumulative incidence function curve with the Kaplan-Meier curve. These curves closely approximated each other. After accounting for the competing risk of noncardiovascular death, the magnitude and direction of the factors associated with cardiovascular death were minimally changed.. Among patients with symptomatic peripheral artery disease, noncardiovascular causes of death reflected a high proportion (40%) of deaths. Accounting for noncardiovascular deaths as a competing risk, there was not a significant change in the risk estimation for cardiovascular death. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

Topics: Aged; Cause of Death; Clopidogrel; Female; Humans; Incidence; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Ticagrelor; Time Factors; Treatment Outcome

Background Peripheral artery disease (PAD) is a known risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention. However, in some studies PAD is not an independent risk factor. We sought to examine the independent impact of PAD on a large prospective percutaneous coronary intervention registry. Methods and Results From our single-center prospective percutaneous coronary intervention registry, we have retrospectively analyzed 25 690 patients (years 2004-2018). We examined the influence of PAD on short- and long-term outcomes using both regression and propensity-matched analyses. Patients with documented PAD (n=1610, 6.3% of total) were older (66.7±10.8 versus 65.4±12.1,

Topics: Aged; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus; Female; Humans; Hypertension; Male; Middle Aged; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Registries; Renal Insufficiency; Retrospective Studies; Risk Factors; Ticagrelor; Treatment Outcome

A combination of antiplatelet drugs with high-intensity statin therapy is a standard in patients with coronary events. Concomitant treatment with ticagrelor, a moderate CYP3A4 inhibitor, and CYP3A4-metabolized statins such as atorvastatin, might lead to an increased risk of muscle-related adverse events. Therefore, investigation of concentrations of these compounds in clinical samples is necessary. For this purpose, an LC-MS/MS method was developed for simultaneous determination of ticagrelor and its active metabolite (AR-C124910XX), as well as 2-hydroxyatorvastatin, which is the main metabolite of atorvastatin. Protein precipitation was used for sample preparation and afterwards the analytes were separated on a Kinetex XB-C18 column with an isocratic elution (water and acetonitrile with 0.1% formic acid, 57:43, v/v). Detection was performed on a triple-quadrupole MS with multiple-reaction-monitoring via electrospray ionization. The method was fully validated according to the EMA's recommendations. Determination was possible within ranges: 1.25-2000 ng/mL for ticagrelor, 1.25-1000 ng/mL for its AR-C124910XX, 1.25-50 ng/mL for atorvastatin and 1.14-45.73 for 2-hydroxyatorvastatin. Within and between-run accuracy, expressed as a relative error, was within 0.05-10.56% for all analytes, while within and between-run precision, expressed as coefficient of variation, was within 0.61-9.91%. Ticagrelor, atorvastatin and their main metabolites were found to be stable in acetonitrile stock solutions, and in plasma samples stored for 24 h at room temperature, 1 month at -25 °C, after 3 cycles of freezing and thawing, and in processed samples stored as a dry residue for 24 h at 4 °C and for 24 h in autosampler at room temperature. This simple and rapid method allowed simultaneous determination of the analytes for the first time. The procedure was applied for the pharmacokinetic study of ticagrelor, its active metabolite AR-C124910XX, and 2-hydroxyatorvastatin in patients simultaneously treated with ticagrelor and atorvastatin.

Topics: Atorvastatin; Chromatography, Liquid; Humans; Limit of Detection; Linear Models; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Reproducibility of Results; Tandem Mass Spectrometry; Ticagrelor

Patients with acute coronary syndrome (ACS) and previous cardiovascular disease (CVD) (stroke, peripheral arterial disease [PAD] or coronary artery disease [CAD]) are at high risk of serious events and mortality. Current clinical guidelines recommend new antiplatelet drugs (NADs) for high cardiovascular risk patients with ACS; however, these drugs are underused in different scenarios.. This study included 1717 ACS patients from 3 tertiary hospitals. Of them, 641 (37.33%) suffered from previous CVD: 149 patients with stroke, 154 patients with PAD and 541 patients with CAD. Bleeding, mortality and major adverse cardiac events (MACE) at 1 year of follow-up after hospital discharge were analyzed.. NADs administration during hospital stay and at discharge was less frequent in patients with previous CVDs (P<0.001, for both). Cox analysis in this cohort of patients showed that clopidogrel prescription at discharge was independently associated with MACEs (HR: 1.59 [95% CI: 1.03-2.45]; P=0.036) and with death (HR: 1.99 [95% CI: 1.00-3.98]; P=0.049) in multivariate analysis. More specifically, when ticagrelor prescription at discharge was compared with clopidogrel, a significant death reduction was found in both, the univariate and the multivariate Cox analysis (HR: 4.54 [95% CI: 2.26-9.13]; P<0.001 and HR: 2.61 [95% CI: 1.16-5.90]; P=0.021, respectively).. New antiplatelet drugs, especially ticagrelor, showed lower rates of mortality in patients with CVD without differences for bleeding. Despite the recommendations of current clinical guidelines for high risk patients with ACS, the use of NADs is very low in "real-life" patients with previous CVD.

Topics: Acute Coronary Syndrome; Aftercare; Clopidogrel; Comorbidity; Coronary Disease; Drug Utilization; Female; Follow-Up Studies; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Metabolic Syndrome; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proportional Hazards Models; Prospective Studies; Smoking; Spain; Stroke; Tertiary Care Centers; Ticagrelor

Topics: Aspirin; Clopidogrel; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Thrombosis; Ticagrelor; Tomography, Optical Coherence

The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear.. To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease.. In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31, 2012, to March 7, 2014; the present post hoc analysis was performed from June 1, 2017, to February 5, 2018.. EUCLID evaluated ticagrelor vs clopidogrel in preventing major adverse cardiac events (cardiovascular death, myocardial infarction [MI], or ischemic stroke) and major bleeding in patients with PAD.. The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. Key secondary end points included the individual components of the primary end point and acute limb ischemia leading to hospitalization, major amputation, and lower-extremity revascularization. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding was also evaluated.. The EUCLID trial randomized 13 885 patients with a median age of 66 years (interquartile range, 60-73 years), of whom 3888 (28.0%) were women. At baseline, 7804 patients (56.2%) had PAD alone; 2639 (19.0%) had PAD + CAD; 2049 (14.8%) had PAD + CVD; and 1393 (10.0%) had PAD + CAD + CVD. Compared with patients with isolated PAD, the adjusted hazard ratios (aHRs) for major adverse cardiac events were 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CVD, 1.65 (95% CI, 1.43-1.91; P < .001) for PAD + CAD, and 1.99 (95% CI, 1.69-2.34; P < .001) for PAD + CAD + CVD. The aHRs for lower-extremity revascularization were 1.17 (95% CI, 1.03-1.34; P = .01) for PAD + CAD, 1.17 (95% CI, 1.02-1.35; P = .02) for PAD + CVD, and 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CAD + CVD. Polyvascular disease was not associated with an increased risk of acute limb ischemia (aHR for PAD + CVD, 0.91; 95% CI, 0.62-1.34, P = .63; PAD + CAD, 0.93; 95% CI, 0.64-1.34, P = .69; and PAD + CAD + CVD, 0.98; 95% CI, 0.63-1.53, P = .93), major amputation (aHR for PAD + CVD, 0.83; 95% CI, 0.54-1.27, P = .40; PAD + CAD, 0.74; 95% CI, 0.47-1.16, P = .19; and PAD + CAD + CVD, 1.12; 95% CI, 0.69-1.80, P = .65), or TIMI major bleeding (PAD + CVD, 0.98; 0.66-1.44, P = .91; PAD + CAD, 1.04; 0.74-1.48, P = .81; and PAD + CAD + CVD, 0.96; 95% CI, 0.62-1.51, P = .88).. Compared with patients with PAD alone, the risk of major adverse cardiac events and lower-extremity revascularization increased with multiple vascular bed involvement. There was no clear increased risk of bleeding associated with polyvascular disease.

Topics: Aged; Female; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Ticagrelor

Topics: Aspirin; Belgium; Clopidogrel; Diabetes Mellitus; Drug Therapy, Combination; Humans; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Stroke; Ticagrelor; Treatment Outcome

Topics: Clopidogrel; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Ticagrelor

Topics: Clopidogrel; Humans; Lower Extremity; Peripheral Arterial Disease; Ticagrelor; Ticlopidine

Topics: Clopidogrel; Humans; Lower Extremity; Peripheral Arterial Disease; Ticagrelor; Vascular Surgical Procedures

Topics: Clopidogrel; Humans; Lower Extremity; Peripheral Arterial Disease; Ticagrelor; Vascular Surgical Procedures

Topics: Clopidogrel; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Ticagrelor; Ticlopidine

The novel P2Y12 antagonist ticagrelor inhibits adenosine diphosphate (ADP)-induced platelet aggregation more potently than clopidogrel and reduces the incidence of myocardial infarction and total death in patients with an acute coronary syndrome (ACS). Furthermore, ticagrelor inhibits adenosine reuptake and increases coronary flow reserve during adenosine infusion in man. We wanted to determine whether ticagrelor improves peripheral arterial function in patients with a previous ACS compared to patients treated with aspirin, clopidogrel, or prasugrel.. 127 patients with a previous ACS (>3 months to <3 years ago) on maintenance dose of (1) no ADP blocker (n = 35); (2) clopidogrel 75 mg (n = 35); (3) prasugrel 10 mg (n = 32), or (4) ticagrelor 90 mg twice daily (n = 25) were evaluated with peripheral arterial tonometry after forearm ischemia.. Ticagrelor improves peripheral arterial function compared to the other groups [(1) controls 1.78 ± 0.53; (2) clopidogrel 1.78 ± 0.45; (3) prasugrel 1.64 ± 0.33, and (4) ticagrelor 2.25 ± 0.54 (means ± SD)] with a significance of p < 0.01 for ticagrelor versus no ADP blocker, p < 0.01 for ticagrelor versus clopidogrel, and p < 0.001 for ticagrelor versus prasugrel. There were fewer patients with endothelial dysfunction (<1.67 reactive hyperemia index) in the ticagrelor group (12%) compared to aspirin (51%), clopidogrel (46%), and prasugrel (53%) (p < 0.01).. Treatment with ticagrelor improves peripheral endothelial function compared to no ADP blocker, clopidogrel, or prasugrel treatment.

Topics: Acute Coronary Syndrome; Adenosine; Aspirin; Blood Pressure; Case-Control Studies; Clopidogrel; Endothelium, Vascular; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Peripheral Arterial Disease; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Topics: Acute Coronary Syndrome; Adenosine; Clinical Trials, Phase III as Topic; Humans; Multicenter Studies as Topic; Peripheral Arterial Disease; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Stroke; Ticagrelor