thienopyridine and Coronary-Artery-Disease

The study aimed to compare the efficacy and safety outcome associated with a short and a prolonged duration of thienopyridine therapy in patients with chronic kidney disease (CKD) after coronary stenting. We systematically searched PubMed, EMBASE and the Cochrane Library from their inception to 1 January 2019 for studies comparing short and prolonged thienopyridine therapy in patients with CKD. Ischemic and bleeding events were considered as the clinical endpoints in this analysis. Odds Ratios (OR) with 95% confidence intervals (CIs) were used as estimates of effect size in random-effect models. Seven studies comprising a total of 17,628 CKD patients were included in the evaluation. Prolonged duration of thienopyridine use, when compared to short-term thienopyridine, was associated with reduced risk of all-cause mortality (odds ratio 0.75, 95% confidence interval: 0.70-0.81,

Topics: Aged; Coronary Artery Disease; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Percutaneous Coronary Intervention; Pyridines; Renal Insufficiency, Chronic; Risk Assessment; Stents; Stroke; Time Factors

Topics: Adenosine; Cardiovascular Diseases; Clopidogrel; Coronary Artery Disease; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Dual antiplatelet therapy with aspirin and clopidogrel, in conjunction with heparin, is the most common antithrombotic strategy in percutaneous coronary intervention (PCI) used to reduce peri-procedural ischaemic complications. However, there remains significant inter-individual variability in post-treatment platelet inhibition with this current established therapy. This review focuses on recent developments in oral antiplatelet agents used in PCI, which promise to overcome, at least in part, current shortfalls.. Genetic polymorphisms and medication interactions involving CYP3A4 or CYP2C19, patient compliance and higher platelet reactivity in certain subgroups, such as those with diabetes, are important factors contributing to inter-individual variability in post-treatment platelet inhibition. Higher clopidogrel doses have been associated with improved clinical outcomes, especially in those presenting with acute coronary syndrome. Newer agents, namely prasugrel and ticagrelor, have been shown to have greater potency and superior clinical outcomes. However, this comes with a price of increased bleeding complications.. Whereas more potent antiplatelet therapies are associated with improved outcome, balancing the risk of bleeding and peri-procedural ischaemic complications remains a key aspect to consider when choosing among the ever-increasing number of agents available. The role of intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) needs to be re-examined in the current context of such potent oral antiplatelet agents. Further research will hopefully help to determine the preferred antithrombotic strategy in patients undergoing PCI.

Topics: Adenosine; Angioplasty, Balloon, Coronary; Aryl Hydrocarbon Hydroxylases; Aspirin; Clopidogrel; Coronary Artery Disease; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Prasugrel Hydrochloride; Pyridines; Risk Factors; Thiophenes; Ticagrelor; Ticlopidine

Antiplatelet therapy is the cornerstone of treatment for patients with coronary artery disease. Since adenosine diphosphate (ADP) represents one of the most important mediators of thrombosis, the inhibition of the platelet ADP receptor, in particular the P2Y₁₂ subtype, plays a pivotal role in secondary prevention of recurrent atherothrombotic events in high-risk settings. Numerous clinical trials have shown the efficacy of clopidogrel, an inhibitor of the ADP P2Y₁₂ receptor, in patients presenting with an acute coronary syndrome and undergoing percutaneous coronary intervention. However, laboratory and clinical experience with clopidogrel have led to understanding some of the limitations of this drug, the most important of which is its broad range in interindividual response variability, resulting in the development of novel ADP P2Y₁₂ receptor-inhibiting strategies. This article provides an overview of ADP P2Y₁₂ receptor-inhibiting strategies, including high clopidogrel dosing regimens and novel agents under advanced clinical development.

Topics: Adenosine Diphosphate; Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Drug Design; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Purinergic P2Y12; Ticlopidine

Thienopyridines have a well-established role in the treatment of coronary artery disease, especially in the setting of acute coronary syndromes and percutaneous coronary interventions. Ticlopidine, the first FDA-approved thienopyridine, was shown to be effective in reducing coronary events in high risk patients, but the original enthusiasm was hampered by concerns about its serious bone marrow toxicity. Clopidogrel a second generation thienopyridine with lesser side effects, is not only at least as effective as ticlopidine, but in combination with a low dose of aspirin, has been demonstrated to reduce the risk of major cardiovascular events in acute coronary syndrome patients in large-scale, randomised trials. Recent studies have highlighted major flaws in clopidogrel pharmacokinetics due to its delayed onset of action, and much attention has been devoted to the phenomenon of clopidogrel 'resistance'. Among the novel, third generation thienopyridines, prasugrel as compared to clopidogrel has demonstrated lower inter-patient response variability and a reduced incidence of ischaemic events, but at an increased risk of major bleeding. Currently, several studies are continuing to test new direct P2Y12 receptor antagonists, such as cangrelor and AZD6140, characterised by a faster reversal of platelet inhibition.

Topics: Animals; Blood Platelets; Clinical Trials as Topic; Coronary Artery Disease; Drug Discovery; Humans; Molecular Structure; Platelet Aggregation Inhibitors; Protein Binding; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Purinergic P2Y12

The recognition that thrombosis is fundamental to acute coronary syndromes (ACS) has inspired the development of novel therapies to inhibit platelet aggregation and thrombus formation. Several recent advances have been made in the management of patients with non-ST-segment elevation ACS (NSTE ACS) to improve early and late clinical outcomes. The research efforts leading to these improvements in care have focused on antiplatelet and anticoagulant therapies coupled with early invasive treatment options. In particular, ongoing clinical trials seek to refine treatment strategies for patients relative to individual risk presentation, the availability of facilities for invasive procedures, and the timing of revascularization. However, even despite the proven efficacy of currently available therapies to reduce the occurrence of death and/or myocardial infarction, still many eligible patients with high-risk NSTE ACS do not receive such treatments. This review provides a pathophysiologic rationale for antithrombotic therapies in ACS, examines the results of recent trials, and presents future directions for clinical investigation.

Topics: Angina, Unstable; Aspirin; Clinical Trials as Topic; Coronary Artery Disease; Heparin, Low-Molecular-Weight; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Thrombolytic Therapy

The platelet has assumed an increasingly important role in cardiovascular medicine as our understanding of the pathophysiology of acute coronary syndromes (ACS) has evolved. Plaque rupture, platelet aggregation, and thrombus formation occur as a result of complex interaction between the platelet, the endothelium, and various inflammatory cells and circulating proteins. Aspirin continues to form the foundation of any anti-ischemic regimen, but cardiologists have long recognized the need for newer, more potent antiplatelet agents. Glycoprotein IIb/IIIa receptor antagonists and thienopryidines have been developed over the past decade and now serve as powerful complements to aspirin in the prevention and treatment of coronary events. The paper will begin with a review of aspirin as well as a discussion of the concept of aspirin resistance. The rapidly expanding body of knowledge supporting the use of glycoprotein IIb/IIIa receptor blockers and thienopyridines will then be addressed, with an emphasis on reconciling recent controversies in the literature. Future advances in the treatment of coronary artery disease will likely occur as we further refine the role of these established antiplatelet drugs and develop agents that bind to novel targets in the thrombotic cascade.

Topics: Aspirin; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines

Antiplatelet drugs have an established place in the prevention of vascular events in a variety of clinical conditions, such as myocardial infarction, stroke and cardiovascular death. Both European and American guidelines recommend the use of antiplatelet drugs in patients with established coronary heart disease and other atherosclerotic disease. In high-risk patients, such as those with post-acute myocardial infarction (AMI), ischaemic stroke or transient ischaemic attack, and in patients with stable or unstable angina, peripheral arterial occlusive disease or atrial fibrillation, antiplatelet treatment may reduce the risk of a serious cardiovascular event by approximately 25%, including reduction of non-fatal myocardial infarction by 1/6, non-fatal stroke by 1/4 and cardiovascular death by 1/6. Some data indicate that antiplatelet drugs may also have a role in primary prevention. In people who are aged over 65 years, or have hypertension, hypercholesterolaemia, diabetes, obesity or familial history of myocardial infarction at young age, aspirin may reduce both cardiovascular deaths and total cardiovascular events. Aspirin has been studied and used most extensively. It may exert its beneficial effect not only by acting on platelets, but also by other mechanisms, such as preventing thromboxane A2 (TXA2)-induced vasoconstriction or reducing inflammation. Indeed, experimental data show that low-dose aspirin may suppress vascular inflammation and thereby increase the stability of atherosclerotic plaque. Moreover, in human studies, aspirin seems to be most effective in those with elevated C-reactive protein levels. Vascular events, however, do occur despite aspirin administration. This may be due to platelet activation by pathways not blocked by aspirin, intake of drugs that interfere with aspirin effect or aspirin resistance. In the CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events) study, long-term clopidogrel administered to patients with atherosclerotic vascular disease was more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction or vascular death. In the setting of coronary stenting, a double regimen including aspirin and ticlopidine or clopidogrel has proved more effective in the prevention of in-stent thrombosis than aspirin alone. Chronic oral administration of the inhibitors of platelet membrane receptor GP IIb/IIIa has been largely disappointing.

Topics: Aspirin; Benzamidines; Clopidogrel; Coronary Artery Disease; Humans; Myocardial Infarction; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Stroke; Ticlopidine; Treatment Outcome

The risk of major adverse cardiac and cerebrovascular events (MACCE) in subjects who interrupt temporarily or permanently thienopyridine therapy in the first 6 months after percutaneous coronary intervention (PCI) remains uncertain. In the dual antiplatelet therapy (DAPT) study subjects were enrolled within 72 hours of PCI and treated with aspirin and a thienopyridine for 12 months before being randomized to continued thienopyridine versus placebo. This analysis focuses on the 12-month period before randomization. Thienopyridine interruptions of greater than 24 hours, occurring in the first 6 months after PCI were evaluated. The incidence of MACCE and moderate or severe bleeding occurring within 12 months after PCI were compared between subjects with and without interruptions. Among 23,002 subjects, the incidence of interruption of thienopyridine was 5.1% (n = 1,173). Compared with subjects who adhered to treatment, subjects with an interruption had a higher incidence of MACCE (6.1% vs 4.3%, p = 0.005), death (2.2% vs 1.4%, p = 0.02), myocardial infarction (3.8% vs 2.7%, p = 0.03), and bleeding (3.1% vs 2.2%, p = 0.04) at 12 months. After adjusting for baseline characteristics, interruptions were associated with MACCE (adjusted odds ratio 1.3, 95% confidence interval 1.0, 1.7, p = 0.04) and had a borderline association with subsequent bleeding (adjusted odds ratio 1.4, 95% confidence interval 1.0, 2.0, p = 0.05). In conclusion, interruption of thienopyridine in the first 6 months after PCI occurs not infrequently and is associated with an increased risk of MACCE and subsequent bleeding between the time of interruption and 12 months after PCI.

Topics: Aged; Aspirin; Combined Modality Therapy; Coronary Angiography; Coronary Artery Disease; Dual Anti-Platelet Therapy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Predictive Value of Tests; Pyridines; Risk Assessment; Stents; Survival Rate; Time Factors; Treatment Outcome; United States; Withholding Treatment

Dual antiplatelet therapy (DAPT) with thienopyridine and aspirin is the standard care for the prevention of stent thrombosis. However, the optimal duration and effect of the duration of DAPT on intra-stent thrombus (IS-Th) formation are unknown. The NIPPON study (Nobori Dual Antiplatelet Therapy as Appropriate Duration) was an open label, randomized multicenter, assessor-blinded, trial designed to demonstrate the non-inferiority of shorter (6-month) DAPT to prolonged (18-month) DAPT, after biolimus A9 eluting stent implantation in 3773 patients at 130 sites in Japan. Among them, 101 patients were randomly allocated for an optical coherence tomography (OCT) sub-study to assess the difference of local IS-Th formation between the two groups. In addition to standard OCT parameters, the number of IS-Th formed was counted in each target stent at 8 months. Baseline patient characteristics were not different between the 6- and 18-month groups. IS-Th was detected in 9.8% of the cases and the presence of IS-Th was not significantly different between the two groups (10.9% in 6-month vs. 9.1% in 12-month, P = 0.76). Furthermore, the number of IS-Th formed was not significantly different between the two groups. This OCT sub-study was in line with the main NIPPON study which demonstrated the non-inferiority of 6-month DAPT to 18-month DAPT. Shorter DAPT duration did not promote progressive IS-Th formation at the mid-term time point.

Topics: Aged; Aspirin; Coronary Artery Disease; Coronary Vessels; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Retrospective Studies; Single-Blind Method; Sirolimus; Time Factors; Tomography, Optical Coherence; Treatment Outcome; Vascular Resistance

Ticagrelor loading dose (LD) increases adenosine plasma levels, which might interfere with fractional flow reserve (FFR) assessment because the latter is based on adenosine-induced hyperemia. In a prospective study, consecutive patients who underwent coronary angiography with at least 1 de novo stenosis >50% and <90% in severity amenable to intervention underwent FFR assessment using intravenous adenosine 140 μg/kg/min for 3 minutes. Patients were subsequently randomized to either ticagrelor 180 mg (n = 38) or control thienopyridine (n = 38) (prasugrel 60 mg [n = 28] or clopidogrel 600 mg [n = 10]), followed by a second FFR assessment of the target lesion 2 hours after drug. Pre-drug, steady hyperemia FFR (sFFR, median, first to third quartiles) was 0.82 (0.75 to 0.88) and 0.81 (0.75 to 0.88), p = 0.9, whereas post-drug, 0.82 (0.72 to 0.87) and 0.79 (0.73 to 0.86), p = 0.5, in thienopyridine and ticagrelor-treated patients, respectively. The primary end point of percent relative change in sFFR between pre- and post-drug periods was greater in ticagrelor- than thienopyridine-treated patients, -1.24 (-5.54 to 0.0) versus -0.51 (-3.68 to 3.21), p = 0.03, respectively. Absolute change in sFFR between pre- and post-drug periods was marginally higher in ticagrelor- than thienopyridine-treated patients -0.01 (-0.04 to 0.0) versus -0.005 (-0.03 to 0.02), p = 0.048, respectively. Reclassification of treatment decision at the sFFR ≤ 0.80 cutoff post-drug occurred in 6 (15.8%) versus 5 (13.2%) of ticagrelor- and thienopyridine-treated patients, respectively. In conclusion, after ticagrelor LD, an absolute and relative reduction in sFFR compared with thienopyridine LD is observed. Administration of ticagrelor should be considered as a potential source, albeit minor, of FFR variability.

Topics: Adenosine; Coronary Angiography; Coronary Artery Disease; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Prospective Studies; Purinergic P2Y Receptor Antagonists; Pyridines; Ticagrelor; Time Factors; Treatment Outcome

The purpose of this study was to characterize outcomes for everolimus-eluting stent (EES)-treated subjects according to treatment with continued thienopyridine plus aspirin versus aspirin alone 12 to 30 months after stenting.. In the DAPT (Dual Antiplatelet Therapy) study, continued thienopyridine plus aspirin beyond 1 year after coronary stenting reduced ischemic events. Given low rates of stent thrombosis and myocardial infarction (MI) for current drug-eluting stents, we examined outcomes among EES-treated subjects in the DAPT study.. The DAPT study enrolled 25,682 subjects (11,308 EES-treated) after coronary stenting. Following 12 months of treatment with thienopyridine and aspirin, eligible subjects continued treatment with aspirin and 9,961 (4,703 with EES) were randomized to 18 months of continued thienopyridine or placebo. Stent type was not randomized, and the EES subset analysis was post hoc.. Among EES-treated patients, continued thienopyridine reduced stent thrombosis (0.3% vs. 0.7%, hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.15 to 0.97; p = 0.04) and MI (2.1% vs. 3.2%, HR: 0.63, 95% CI: 0.44 to 0.91; p = 0.01) versus placebo but did not reduce a composite of death, MI, and stroke (4.3% vs. 4.5%, HR: 0.89, 95% CI: 0.67 to 1.18; p = 0.42), and increased moderate/severe bleeding (2.5% vs. 1.3%, HR: 1.79, 95% CI: 1.15 to 2.80; p = 0.01), and death (2.2% vs. 1.1%, HR: 1.80, 95% CI: 1.11 to 2.92; p = 0.02). Death due to cancer and not related to bleeding was increased (0.64% vs. 0.17%; p = 0.01).. In EES-treated subjects, significant reductions in stent thrombosis and MI and an increase in bleeding were observed with continued thienopyridine beyond 1 year compared with aspirin alone. (The Dual Antiplatelet Therapy Study [DAPT Study]); NCT00977938).

Topics: Aged; Aspirin; Cardiovascular Agents; Coronary Artery Disease; Coronary Thrombosis; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Drug-Eluting Stents; Everolimus; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prosthesis Design; Pyridines; Risk Factors; Time Factors; Treatment Outcome

Previous data suggest that reticulated platelets significantly affect antiplatelet response to thienopyridines. It is unknown whether parameters describing reticulated platelets can predict antiplatelet response to thienopyridines.. The authors sought to determine the extent to which parameters describing reticulated platelets can predict antiplatelet response to thienopyridine loading compared with established predictors.. This study randomized 300 patients undergoing elective coronary stenting to loading with clopidogrel 600 mg, prasugrel 30 mg, or prasugrel 60 mg. Adenosine diphosphate (ADP)-induced platelet reactivity was assessed by impedance aggregometry before loading (intrinsic platelet reactivity) and again on day 1 after loading. Multiple parameters of reticulated platelets were assessed by automated whole blood flow cytometry: absolute immature platelet count (IPC), immature platelet fraction, and highly fluorescent immature platelet fraction.. Each parameter of reticulated platelets correlated significantly with ADP-induced platelet reactivity (p < 0.01 for all 3 parameters). In a multivariable model including all 3 parameters, only IPC remained a significant predictor of platelet reactivity (p < 0.001). In models adjusting each of the 3 parameters for known predictors of on-treatment platelet reactivity including cytochrome P450 2C19 (CYP2C19) polymorphisms, age, body mass index, diabetes, and intrinsic platelet reactivity, only IPC prevailed as an independent predictor (p = 0.001). In this model, IPC was the strongest predictor of on-treatment platelet reactivity followed by intrinsic platelet reactivity.. IPC is the strongest independent platelet count-derived predictor of antiplatelet response to thienopyridine treatment. Given its easy availability, together with its even stronger association with on-treatment platelet reactivity compared with known predictors, including the CYP2C19*2 polymorphism, IPC may become the preferred predictor of antiplatelet response to thienopyridine treatment. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate-Advanced Loading Strategies [ExcelsiorLOAD]; DRKS00006102).

Topics: Aged; Blood Platelets; Coronary Artery Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Count; Pyridines; Stents; Treatment Outcome

On-treatment platelet reactivity (OTR) is a predictor of clinical outcomes in patients receiving thienopyridine therapy.. To assess whether point-of-care platelet reactivity testing can discriminate between patients who have and have not received a thienopyridine.. This was an analysis of a randomized, multicenter, pharmacodynamic trial. Subjects with coronary artery disease treated with aspirin were randomly assigned to clopidogrel 75 mg daily or prasugrel 10 mg daily for 7 days. Platelet reactivity assessment with the VerifyNow P2Y12 test was performed before study drug admistration and 24 h after the final dose. Optimal cut-offs for a detectable drug effect were identified by the use of receiver operating characteristic curve analysis.. A total of 54 subjects were enrolled and completed the study. The c-statistic for the identification of a thienopyridine effect was highly significant (0.93, P < 0.001), including for the clopidogrel and prasugrel groups considered separately (P < 0.001 for both). The optimal cut-off was < 213 P2Y12 reaction units (PRU), which provided a sensitivity of 80% and a specificity of 98%. This cut-off provided a sensitivity of 58% and a specificity of 100% for a clopidogrel effect, and a sensitivity of 100% and specificity of 96% for a prasugrel effect.. OTR of < 213 PRU is highly specific for exposure to either clopidogrel or prasugrel. This may be useful in the management of thienoypridine-treated patients who require surgery. Furthermore, this diagnostic cut-off is similar to levels of OTR that have been associated with ischemic events in thienopyridine-treated patients, supporting the contention that a lack of drug effect is the mechanistic basis for the prognostic relationship between OTR and clinical outcomes.

Topics: Aged; Aspirin; Blood Platelets; Clopidogrel; Coronary Artery Disease; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperazines; Platelet Activation; Point-of-Care Systems; Prasugrel Hydrochloride; Pyridines; Receptors, Purinergic P2Y12; Reproducibility of Results; ROC Curve; Sensitivity and Specificity; Thiophenes; Ticlopidine; Time Factors; Treatment Outcome

Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial.. This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6-18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411.. Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15-18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68-2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02-1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07-0·91]; p=0·04).. Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment.. Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

Topics: Adolescent; Adult; Aged; Aspirin; Coronary Artery Disease; Drug Administration Schedule; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Pyridines; Treatment Outcome; Young Adult

Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

Topics: Aged; Alleles; Aryl Hydrocarbon Hydroxylases; Aryldialkylphosphatase; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biotransformation; Blood Platelets; Cell Adhesion Molecules; Cells, Cultured; Clopidogrel; Coronary Artery Disease; Cytochrome P-450 CYP2C19; Female; Humans; Male; Microfilament Proteins; Middle Aged; Phosphoproteins; Piperazines; Platelet Activation; Polymorphism, Genetic; Prasugrel Hydrochloride; Prospective Studies; Pyridines; Receptors, Purinergic P2Y12; Thiophenes; Ticlopidine

Rates of stent thrombosis (ST) after ST-elevation myocardial infarction (STEMI) may vary over time and the relationship of this complication with non-adherence to dual antiplatelet therapy (DAPT) during long-term follow-up remains unclear.. We analysed 2,997 patients who were treated with at least one stent and in whom a non-target vessel ST did not occur during follow-up from the large-scale Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial of patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Aspirin was prescribed indefinitely, and a thienopyridine for at least six months. DAPT usage was evaluated according to the development of ST in four time periods (<1 month, 1-6 months, 6-12 months and >1 year from index stent implantation). DAPT non-usage was lowest within the first month, but was strongly associated with ST. During the 1-6 month period the relationship remained strong, but was absent in the 6-12 month period. Beyond one year, ST was associated with non-usage of aspirin but was paradoxically more common in patients taking a thienopyridine.. The relationship between stent thrombosis and non-adherence to DAPT varies over time. It is strong within the first month, remains important until six-month follow-up but fades afterwards. Very late ST is associated with both DAPT and aspirin alone but not with thienopyridine non-adherence.

Topics: Aspirin; Coronary Artery Disease; Coronary Thrombosis; Drug Therapy, Combination; Drug-Eluting Stents; Electrocardiography; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Patient Compliance; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Surveys and Questionnaires; Treatment Outcome

We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes.. Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel.. In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo.. The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo.. Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.

Topics: Adult; Aged; Clopidogrel; Comorbidity; Coronary Artery Disease; Diabetes Complications; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prevalence; Pyridines; Thiophenes; Ticlopidine; Treatment Failure; Treatment Outcome

Adjunctive glycoprotein IIb/IIIa inhibition decreases ischemic events after percutaneous coronary intervention (PCI) but is associated with increased bleeding. We hypothesized that maximal antiplatelet therapy with aspirin, a thienopyridine, and a glycoprotein IIb/IIIa inhibitor without unfractionated heparin (UFH) would result in fewer bleeding complications and maintain efficacy in elective PCI. A total of 159 patients undergoing elective PCI were randomized to intraprocedural eptifibatide alone or eptifibatide plus UFH. Patients received aspirin 325 mg and clopidogrel 300 mg before the procedure. The primary end point was the Landefeld bleeding index. Secondary end points included the composite clinical outcome of in-hospital death, myocardial infarction, urgent target vessel revascularization, and Thrombolysis In Myocardial Infarction major bleeding, and a composite bleeding outcome of major, minor, and nuisance bleeding. The Landefeld bleeding index was significantly lower in the eptifibatide-only group compared with the eptifibatide-plus-UFH group (3.0 vs 3.9, p = 0.03). There was no significant difference in the composite clinical end point between groups (eptifibatide only 17% vs eptifibatide plus UFH 15%, p = 0.7). There was a trend toward a decrease in the composite bleeding end point in the eptifibatide-only compared with the eptifibatide-plus-UFH group (43% vs 56%, p = 0.10). In conclusion, during elective PCI, a strategy of aggressive antiplatelet therapy using aspirin, clopidogrel, and eptifibatide without anticoagulant therapy appears to decrease bleeding complications.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Clopidogrel; Coronary Artery Disease; Drug Therapy, Combination; Eptifibatide; Female; Heparin; Humans; Male; Middle Aged; Peptides; Pilot Projects; Platelet Aggregation Inhibitors; Prospective Studies; Pyridines; Ticlopidine; Treatment Outcome

Lower gastrointestinal bleeding (LGIB) is a common complication for patients with coronary artery disease (CAD) due to the use of antithrombotic medications. Limited data exist describing which patients are at increased risk for mortality.. This study aims to (i) determine whether patients on dual antiplatelet therapy (DAPT) or triple therapy are at higher risk of 90-day and 6-month mortality compared with patients on aspirin alone and (ii) evaluate risk factors for mortality in patients with CAD on antithrombotics hospitalized with LGIB.. We conducted a retrospective cohort study of patients hospitalized with LGIB and CAD while on aspirin at a single academic medical center from 2007 to 2015. Patients were identified using a validated, machine-learning algorithm and classified by use of aspirin, DAPT, or triple therapy. Univariate and multivariate Cox proportional hazards were used to determine mortality associated risk factors.. Seven hundred sixteen patients were identified with LGIB and CAD. Four hundred seventy-two (65.9%) patients were on aspirin monotherapy, 179 (25%) on aspirin and thienopyridine (DAPT), and 65 (9.1%) on aspirin, thienopyridine, and systemic anticoagulant (triple therapy). On univariate analysis, triple therapy use was associated with increased risk of 90-day (hazard ratio [HR] 3.12, 95% confidence interval [CI] 1.52-5.92, P = 0.003) and 6-month (HR 2.46, 95%CI 1.29-4.35, P = 0.008) mortality. Holding anticoagulation was associated with higher mortality at 90 days (HR 2.30, 95%CI 1.27-4.07, P = 0.007). On multivariate analysis, after adjusting for confounding variables, the use of triple therapy remained associated with higher 90-day mortality (HR 3.23, 95%CI 1.56-6.16, P = 0.003).. Triple therapy is associated with mortality at 90 days and at 6 months post discharge.

Topics: Aged; Anticoagulants; Aspirin; Cohort Studies; Coronary Artery Disease; Drug Therapy; Female; Fibrinolytic Agents; Gastrointestinal Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Multivariate Analysis; Pyridines; Retrospective Studies; Risk; Risk Factors; Time Factors

Early cardiovascular and bleeding events after coronary stenting are associated with high risk of morbidity and mortality.. To assess the prognosis of cardiovascular and bleeding events occurring beyond 1 year after coronary stenting.. This secondary analysis is derived from data from the Dual Antiplatelet Therapy (DAPT) Study, a multicenter trial involving 220 US and international clinical sites from 11 countries. The study dates were August 2009 to May 2014. Individuals who underwent coronary stenting and completed 12 months of thienopyridine plus aspirin therapy without ischemic or bleeding events remained on an aspirin regimen and were randomized to continued thienopyridine therapy vs placebo for 18 additional months. Individuals were then followed up for 3 additional months while receiving aspirin therapy alone. The analysis began in August 2015.. Ischemic events (myocardial infarction not related to stent thrombosis, stent thrombosis, and ischemic stroke) and bleeding events (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries [GUSTO] classification moderate or severe bleeding).. Ischemic events (myocardial infarction not related to stent thrombosis, stent thrombosis, and ischemic stroke) and bleeding events (GUSTO classification moderate or severe bleeding). Death at 21 months after randomization (33 months after coronary stenting).. In total, 25 682 individuals older than 18 years with an indication for coronary stenting were enrolled, and 11 648 (mean age, 61.3 years; 25.1% female) were randomized. After randomization, 478 individuals (4.1%) had 502 ischemic events (306 with myocardial infarction, 113 with stent thrombosis, and 83 with ischemic stroke), and 232 individuals (2.0%) had 235 bleeding events (155 with moderate and 80 with severe bleeding). Among individuals with ischemic events, 52 (10.9%) died. The annualized mortality rate after an ischemic event was 27.2 (95% CI, 20.3-35.7) per 100 person-years. The cumulative incidence of death after an ischemic event among the total randomized study population was 0.5% (0.3% with myocardial infarction, 0.1% with stent thrombosis, and 0.1% with ischemic stroke). Among individuals with bleeding events, 41 (17.7%) died. The annualized mortality rate after a bleeding event was 21.5 (95% CI, 15.4-29.1) per 100 person-years. The cumulative incidence of death after a bleeding event among the total randomized study population was 0.3% (0.1% with moderate and 0.2% with severe bleeding).. In patients treated with dual antiplatelet therapy for at least 1 year after coronary stenting, ischemic events were more frequent than bleeding events, and both events were associated with high risk of mortality.. clinicaltrials.gov Identifier: NCT00977938.

Topics: Aged; Aspirin; Brain Ischemia; Coronary Artery Disease; Coronary Thrombosis; Drug Therapy, Combination; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Mortality; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Care; Pyridines; Stents; Stroke

The role of triple antithrombotic therapy vs dual antithrombotic therapy in patients with both atrial fibrillation and coronary artery disease remains unclear. This study explores the differences in treatment practices and outcomes between triple antithrombotic therapy and dual antithrombotic therapy in patients with atrial fibrillation and coronary artery disease.. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (n = 10,135), we analyzed outcomes in patients with coronary artery disease (n = 1827) according to treatment with triple antithrombotic therapy (defined as concurrent therapy with an oral anticoagulant, a thienopyridine, and aspirin) or dual antithrombotic therapy (comprising either an oral anticoagulant and one antiplatelet agent [OAC plus AA] or 2 antiplatelet drugs and no anticoagulant [DAP]).. The use of triple antithrombotic therapy, OAC plus AA, and DAP at baseline was 8.5% (n = 155), 80.4% (n = 1468), and 11.2% (n = 204), respectively. Among patients treated with OAC plus AA, aspirin was the most common antiplatelet agent used (90%), followed by clopidogrel (10%) and prasugrel (0.1%). The use of triple antithrombotic therapy was not affected by patient risk of either stroke or bleeding. Patients treated with triple antithrombotic therapy at baseline were hospitalized for all causes (including cardiovascular) more often than patients on OAC plus AA (adjusted hazard ratio 1.75; 95% confidence interval, 1.35-2.26; P <.0001) or DAP (hazard ratio 1.82; 95% confidence interval, 1.25-2.65; P = .0018). Rates of major bleeding or a combined cardiovascular outcome were not significantly different by treatment group.. Choice of antithrombotic therapy in patients with atrial fibrillation and coronary artery disease was not affected by patient stroke or bleeding risks. Triple antithrombotic therapy-treated patients were more likely to be hospitalized for all causes than those on OAC plus AA or on DAP.

Topics: Administration, Oral; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Comorbidity; Coronary Artery Disease; Drug Therapy, Combination; Female; Fibrinolytic Agents; Hospitalization; Humans; Male; Markov Chains; Monte Carlo Method; Myocardial Infarction; Outcome and Process Assessment, Health Care; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Pyridines; Registries; Stroke; Ticlopidine; Warfarin

Patients with diabetes mellitus (DM) experience higher rates of in-stent restenosis and greater benefit from drug-eluting stents implant at the time of percutaneous coronary intervention (PCI), necessitating prolonged dual anti-platelet therapy (DAPT). While DAPT reduces risk of ischemic events post-PCI, it also increases risk of bleeding. Whether bleeding rates differ among patients with and without DM, receiving long-term DAPT is unknown.. Among patients who underwent PCI and were maintained on DAPT for 1 year in a multicenter US registry, we assessed patient-reported bleeding over one year following PCI in patients with and without DM. Multivariable, hierarchical Poisson regression was used to evaluate the association of DM with bleeding during follow-up.. Among 2334 PCI patients from 10 US hospitals (mean age 64, 54% ACS), 32.6% had DM. In unadjusted analyses, patients with DM had fewer bleeding events over the year following PCI (DM vs no DM: BARC = 1: 78.0% vs 87.7%, P < .001; BARC ≥2: 4.3% vs 5.3%, P = .33). Following adjustment, patients with (vs without DM) had a lower risk of BARC ≥1 bleeding during follow-up (relative risk [RR] 0.89, 95% CI 0.83-0.96). This decreased bleeding risk persisted after removing bruising from the endpoint definition.. In a real-world PCI registry, patients with DM experienced lower risk of bleeding risk on DAPT. As patients with DM also derive greater ischemic benefit from drug-eluting stents, which requires prolonged DAPT, our findings suggest that the balance between benefit and risk of this therapeutic approach may be even more favorable in patients with DM than previously considered.

Topics: Aged; Aspirin; Comorbidity; Coronary Artery Disease; Diabetes Mellitus; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hemorrhage; Humans; Long Term Adverse Effects; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Registries; Risk Assessment

The optimal antithrombotic regimen in patients with atrial fibrillation (AF) undergoing drug-eluting stent (DES) implantation for complex coronary artery disease is unclear. We compared the net clinical outcomes of triple antithrombotic therapy (TAT; aspirin, thienopyridine, and warfarin) and dual antiplatelet therapy (DAPT; aspirin and thienopyridine) in AF patients who had undergone DES implantation.. A total of 367 patients were enrolled and analyzed retrospectively; 131 patients (35.7%) received TAT and 236 patients (64.3%) received DAPT. DAPT and warfarin were maintained for a minimum of 12 and 24 months, respectively. The primary endpoint was the 2-year net clinical outcomes, a composite of major bleeding and major adverse cardiac and cerebral events (MACCE). Propensity score-matching analysis was carried out in 99 patient pairs.. The 2-year net clinical outcomes of the TAT group were worse than those of the DAPT group (34.3 vs. 21.1%, P=0.006), which was mainly due to the higher incidence of major bleeding (16.7 vs. 4.6%, P<0.001), without any significant increase in MACCE (22.1 vs. 17.7%, P=0.313). In the multivariate analysis, TAT was an independent predictor of worse net clinical outcomes (odds ratio 1.63, 95% confidence interval 1.06-2.50) and major bleeding (odds ratio 3.54, 95% confidence interval 1.65-7.58). After propensity score matching, the TAT group still had worse net clinical outcomes and a higher incidence of major bleeding compared with the DAPT group.. In AF patients undergoing DES implantation, prolonged administration of TAT may be harmful due to the substantial increase in the risk for major bleeding without any reduction in MACCE.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebrovascular Disorders; Chi-Square Distribution; Coronary Artery Disease; Drug Therapy, Combination; Female; Fibrinolytic Agents; Hemorrhage; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Odds Ratio; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Propensity Score; Proportional Hazards Models; Pyridines; Republic of Korea; Retrospective Studies; Risk Factors; Stents; Time Factors; Treatment Outcome; Warfarin

The incidence of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy is currently increasing. However, the predictors of small bowel bleeding (SBB) associated with NSAIDs are unknown. This study aimed to assess the risk factors of SBB in chronic NSAIDs users.. We retrospectively compared the medical records of 147 patients receiving NSAIDs in a tertiary-care setting (31 with SBB and 116 without previous bleeding events) and analyzed the predictors of SBB.. In total, 31 patients underwent video capsule endoscopy to detect SBB, 74.2% of whom showed the evidence of SBB. Non-invasive treatment was performed in 90.3% of the patients. Multivariate logistic regression analysis revealed that the presence of coronary artery disease [adjusted odds ratio (aOR) 12.43, 95% confidence interval (CI) 1.19-130.34, P = 0.04], use of thienopyridine (aOR 16.93, 95% CI 3.78-75.72, P < 0.001) and prior use of rebamipide (aOR 0.31, 95% CI 0.12-0.82, P = 0.02) were independently associated with SBB in NSAIDs users.. Coronary artery disease and co-use of thienopyridine were associated with SBB in NSAIDs users. The patients with coronary artery disease co-using thienopyridine need to be monitored for the occurrence of SBB when they were prescribed with NSAIDs.

Topics: Aged; Alanine; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Capsule Endoscopy; Coronary Artery Disease; Female; Gastrointestinal Hemorrhage; Humans; Incidence; Intestine, Small; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Quinolones; Retrospective Studies; Risk Factors

Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Each year, millions of patients undergo stent placement to treat coronary artery disease. As stents are prone to thrombosis, which can potentially be devastating, patients are treated with dual antiplatelet therapy with aspirin plus a thienopyridine for at least 6-12 months after stent placement. New evidence suggests that long-term dual antiplatelet therapy beyond 1 year prevents ischemic events but also leads to increased risk of bleeding. To determine the optimal strategy for dual antiplatelet therapy after stent placement, the benefits and risks must be carefully considered and individualized for each patient.

Topics: Aspirin; Coronary Artery Disease; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Pyridines; Risk; Stents; Thrombosis

Optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation has not been yet fully elucidated.. We assessed the influence of prolonged thienopyridine therapy on clinical outcomes with landmark analysis at 4 and 13 months after DES implantation. Among 6802 patients with at least 1 DES implantation in the CREDO-Kyoto Registry Cohort-2, 6309 patients (on thienopyridine, 5438 patients; off thienopyridine, 871 patients) and 5901 patients (on thienopyridine, 4098 patients; off thienopyridine, 1803 patients) were eligible for the 4- and 13-month landmark analyses, respectively. The majority of patients had stable coronary artery disease (73%) and received sirolimus-eluting stents (93%), and approximately 90% of thienopyridine was ticlopidine. Patients taking thienopyridine had more complex comorbidities and more complex lesion and procedural characteristics as compared with patients not taking thienopyridine. After adjusting for confounders, thienopyridine use was not associated with decreased risk for death/myocardial infarction/stroke (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.89-1.43, P=0.32 in the 4-month landmark analysis; HR, 1.14; 95% CI, 0.90-1.45, P=0.29 in the 13-month landmark analysis, respectively), whereas the risk for GUSTO moderate/severe bleeding tended to be higher in patients taking thienopyridine (HR, 1.51; 95% CI, 1.00-2.23, P=0.049 in the 4-month landmark analysis; HR, 1.44; 95% CI, 0.99-2.09, P=0.057 in the 13-month landmark analysis, respectively).. Prolonged thienopyridine therapy beyond 4 and 13 months appeared not to be associated with reduction in ischemic events but to be associated with a trend toward increased bleeding. Optimal duration of DAPT after DES implantation might be shorter than the currently recommended 1-year interval.

Topics: Aged; Angioplasty, Balloon, Coronary; Aspirin; Chi-Square Distribution; Clopidogrel; Cohort Studies; Coronary Artery Disease; Drug Administration Schedule; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prosthesis Design; Pyridines; Registries; Stroke; Ticlopidine; Time Factors; Treatment Outcome

Due to serious concerns on very late stent thrombosis (VLST), extended use of dual antiplatelet therapy (DAPT) beyond 1 year after DES implantation has become a common clinical practice despite apparent lack of evidence suggesting its efficacy in reducing VLST. The study population consisted of 12812 patients in the j-Cypher registry who were treated with at least one sirolimus-eluting stent (SES). We assessed the relation between duration of thienopyridine therapy and clinical outcomes with a landmark analysis at 1 year after SES implantation. Among 11713 patients without myocardial infarction (MI), stent thrombosis and stroke at 1 year who were eligible for the landmark analysis, 7414 patients (63 %) were maintained on thienopyridine at 1-year landmark point, while 4299 patients (37 %) had discontinued thienopyridine before 1-year landmark point. Patients in the on-thienopyridine group had more complex characteristics than patients in the off-thienopyridine group. Cumulative incidence of and the risk for definite VLST in the on-thienopyridine group relative to the off-thienopyridine group favored prolonged DAPT, but were not significant [0.9 and 1.2 %, P = 0.1, and adjusted HR (95 % CI): 0.71 (0.47-1.06), P = 0.11]. Cumulative incidence of and the risk for a composite of death, MI, or stroke in the on-thienopyridine group relative to the off-thienopyridine group were also not significant [15.3 and 14.3 %, P = 0.15, and adjusted HR (95 % CI): 0.99 (0.89-1.11), P = 0.89]. Prolonged use of thienopyridine beyond 1 year after SES implantation was not associated with significant decrease in the risks for VLST or for serious cardiovascular events including death, MI or stroke.

Topics: Aged; Aged, 80 and over; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Pyridines; Registries; Sirolimus; Thrombosis; Treatment Outcome

Few studies have examined whether high-responsiveness to antiplatelet therapy is associated with an increased risk of bleeding in patients receiving dual antiplatelet therapy.. Elective drug-eluting stent implantation was performed in 184 patients treated with aspirin and a thienopyridine (200 mg/day of ticlopidine or 75 mg/day of clopidogrel). The subjects were divided into 3 groups according to post-treatment platelet reactivity before stenting as measured by the response to adenosine diphosphate: the 1(st) quartile group was defined as high-responders, the 4(th) as low-responders, and the other 2 quartiles as middle-responders. Major bleeding occurred more frequently in high-responders than in middle- or low-responders during an average of 16 months' follow-up (15 vs 4, 2%, P=0.02). High-responsiveness was the independent predictor of major bleeding (odds ratio 4.26, P=0.03). Adverse cardiac events were less frequent in high- and middle-responders than in low-responders (24, 16 vs 37%, P=0.02). Middle-responders had better net clinical outcomes, defined as the sum of major bleeding and adverse cardiac events, than did high- or low-responders (21 vs 39, 39%, P=0.02).. In the present study high-responsiveness to antiplatelet therapy was associated with an increased risk of bleeding with no reduction in adverse cardiac events. Measuring platelet reactivity may be useful for risk stratification according to bleeding complications, as well as adverse cardiac events, in patients treated with drug-eluting stents.

Topics: Aged; Angioplasty, Balloon, Laser-Assisted; Aspirin; Clopidogrel; Coronary Artery Disease; Drug Therapy, Combination; Drug-Eluting Stents; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Pyridines; Retrospective Studies; Risk Factors; Ticlopidine; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Bypass; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Pyridines; Stroke

Topics: Clopidogrel; Coronary Artery Disease; Diabetes Mellitus; Disease Progression; Drug-Eluting Stents; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Ticlopidine; Time Factors; Treatment Outcome

Significant advances in interventional cardiology have occurred over the past 30 years, leading to substantial increases in the number and anatomic complexity of treated patients, the long-term success of these procedures, and a reduction in the need for coronary bypass surgery. While the risk ofrestenosis has been dramatically reduced by drug-eluting stents, delayed neo-intimal healing has led to a small, but significant occurrence of "late" stent thrombosis. This thrombotic risk is substantially reduced by continuation of dual-anti-platelet therapy for one or more years following DES placement. Current guidelines for patient selection for DES, for duration of DAT following DES, and for facing surgical and invasive procedures after DES were discussed, and the avoidance of early discontinuation of anti-platelet therapy following DES was emphasized.

Topics: Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Aspirin; Consensus; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Paclitaxel; Platelet Aggregation Inhibitors; Pyridines; Sirolimus

Topics: Blood Platelets; Clopidogrel; Coronary Artery Disease; Diabetes Complications; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Risk Factors; Thiophenes; Ticlopidine; Treatment Failure

Although periprocedural drug therapy has been shown to improve the outcome of percutaneous coronary intervention (PCI), information regarding its use in daily clinical practice is limited.. We conducted a national survey on periprocedural drug therapy across the spectrum of PCI practice in Italy. Seventy-nine centers (41% of the Italian interventional cath labs) with a fair distribution across the country volunteered to enroll consecutive patients undergoing PCI for any indication from September 15 to 29, 2003.. Of the 1517 patients enrolled, 745 (49 %) had stable coronary disease and 772 (51%) acute coronary syndromes (ACS): 457 without and 315 with ST-segment elevation. Stenting was used in 89% of cases. N-acetylcysteine was used in 23% of the patients with preexisting renal dysfunction. Thienopyridine (63% clopidogrel) pretreatment was given in 49 % of the cases and, at logistic regression analysis, was independently associated with prior myocardial infarction (p < 0.001), prior PCI (p = 0.007), stable coronary disease (p = 0.005), and treatment in northern Italy (p < 0.05). Platelet glycoprotein (GP) IIb/IIIa receptor blockers (50% abciximab 50% tirofiban) were used in 22% of the stable patients and 40 % of those with ACS, a proportion increasing to 62 % when PCI was undertaken as an emergency procedure. Off-label use of these drugs was frequent (direct cath lab use of tirofiban in 55% of the cases; bailout use: 16% with abciximab and 26% with tirofiban). At logistic regression analysis, independent predictors of GP IIb/IIIa receptor blocker use were emergency procedure (odds ratio 3.6, 95 % confidence interval 2.6 to 5.0, p < 0.0001) and treatment for an ACS (odds ratio 1.6, 95% confidence interval 1.3 to 2.1, p = 0.0002). An emergency procedure was the only independent predictor for the use of abciximab instead of tirofiban (odds ratio 4.1, 95% confidence interval 2.6 to 6.5, p < 0.0001). Triple periprocedural antiplatelet therapy, including aspirin, a thienopyridine and a GP IIb/IIIa receptor blocker was administered in only 21% of cases. At discharge, all stented patients received aspirin and a thienopyridine. Despite complete procedural success in > 90% of cases, 50% of the patients were discharged on symptomatic anti-ischemic therapy.. A wide gap exists between guideline recommendations and periprocedural drug therapy in PCI, the only exception being full prescription of aspirin and a thienopyridine at discharge after stenting. In patients with ACS, thienopyridine pretreatment is often used as a surrogate for GP IIb/IIIa blockade, whose use rather is associated with emergency procedures. Off-label use of drugs is not uncommon.

Topics: Acetylcysteine; Adrenergic beta-Antagonists; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Clopidogrel; Coronary Artery Disease; Drug Utilization Review; Female; Health Care Surveys; Heparin; Humans; Italy; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Practice Guidelines as Topic; Pyridines; Registries; Ticlopidine