thienopyridine and Thrombosis

Coronary stent implantation, particularly drug eluting stents, is now the major method of coronary revascularisation. Following drug-eluting stent implantation dual antiplatelet therapy with aspirin and thienopyridine is recommended for at least 12 months. Premature discontinuation, often at the time of noncardiac surgery, has been associated with stent thrombosis which has a significant risk of death and myocardial infarction. Late (>30 days) and very late (>365 days) stent thrombosis appears to more common with DES and poses the questions of when is it safe to stop antiplatelet therapy post coronary stenting and how to manage patients who need non-cardiac surgery. This article reviews the evidence for stent thrombosis and the peri-operative management of patients with coronary stents and provides an algorithm for patient management based on multidisciplinary assessment of bleeding risk, perioperative cardiac event and stent thrombosis risk.

Topics: Drug-Eluting Stents; Humans; Myocardial Infarction; Myocardial Reperfusion; Perioperative Care; Platelet Aggregation Inhibitors; Pyridines; Risk Factors; Thrombosis; Time Factors

Topics: Aspirin; Atherosclerosis; Clopidogrel; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Pyridines; Thrombosis; Ticlopidine

Acute coronary syndrome (ACS) is associated with a persistent prothrombotic state, placing patients at high risk of subsequent ischemic events. Guidelines recommend the use of dual antiplatelet therapy with aspirin + a thienopyridine (clopidogrel) for at least a year after ACS in most patients, except those who undergo coronary artery bypass grafting. Clinical studies demonstrate that this strategy significantly reduces the risk of ischemic events at the expense of a small increase in the risk of bleeding. Physicians must balance the risk of bleeding against the benefit of ischemia prevention, bearing in mind that ischemic events are generally more common than major bleeding and often associated with more catastrophic consequences or ongoing morbidity. The relationship between bleeding and mortality is complicated by the fact that many risk factors for bleeding are also those for mortality and that bleeding may lead to discontinuation of antiplatelet therapy, thereby increasing the risk for an ischemic event. Data suggest that physicians tend to overestimate the risk of bleeding and underestimate the risk of ischemia. Careful patient selection and thorough patient education are the keys to managing antiplatelet therapy after ACS, especially as newer more potent antiplatelet agents, such as prasugrel, become available.

Topics: Acute Coronary Syndrome; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Artery Bypass; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Risk Factors; Thiophenes; Thrombosis; Ticlopidine

Oral antiplatelet therapy with aspirin and clopidogrel is a major strategy to prevent thrombotic events in patients with acute coronary syndromes and patients undergoing percutaneous coronary interventions. Although this therapy is associated with both short- and long-term clinical efficacy, irreversible platelet inhibition and ischemic events associated with premature withdrawal especially in patients treated with drug-eluting stents constitute a particular limitation in patients undergoing surgery. The current review article is focused on the central role of platelets in the occurrence of ischemic events, the significance of antiplatelet therapy, the potential hazards of drug withdrawal in patients needing coronary artery bypass grafting, and future perspectives.

Topics: Administration, Oral; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Artery Bypass; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Thiophenes; Thrombosis; Ticlopidine

In a series of articles the authors consider clinical pharmacology and experience of clinical application of blockers of platelet P2Y12 receptors, most well known representatives of which ticlopidine and clopidogrel according to chemical structure belong to thienopyridine derivatives. In the fifth communication we consider data of two randomized studies in which efficacy and safety of clopidogrel in combination with acetylsalicylic acid (ASA) has been assessed in comparison with ASA in stable patients with atherothrombotic cardiovascular disease. It has been shown in both studies that in stable patients with atherothrombotic cardiovascular disease long-term therapy with combination of clopidogrel and ASA was no more effective than monotherapy with ASA or clopidogrel but was associated with high risk of hemorrhagic complications. Thus contrary to acute coronary syndromes and percutaneous interventions with stenting combinations of clopidogrel and ASA is not indicated to patients with stable course cardiovascular diseases.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Arteriosclerosis; Aspirin; Cardiovascular Diseases; Clopidogrel; Coronary Circulation; Death, Sudden, Cardiac; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Risk Factors; Sex Factors; Streptokinase; Stroke; Thrombosis; Ticlopidine; Time Factors

Antiplatelet therapy is often discontinued in patients with drug-eluting stents who are undergoing surgical procedures. However, discontinuation of antiplatelet therapy is an important risk factor for late stent thrombosis. Our objective was to examine the safety of short-term discontinuation of antiplatelet therapy.. We systematically searched Medline for reported cases of late stent thrombosis and very late stent thrombosis published between January 2001 and July 2008. We restricted our search to Academic Research Consortium-defined definite cases. We identified 161 cases of late stent thrombosis or very late stent thrombosis from 84 articles (79 from case reports, 61 from registries, and 21 from randomized clinical trials). Patients had a mean age of 58.4+/-13.4 years, and 88% were male. A total of 19 cases occurred in patients who were receiving dual antiplatelet therapy at the time of the event. If patients stopped both antiplatelet agents simultaneously, the median time to event was 7 days. If patients had previously stopped a thienopyridine with no ill effect and subsequently stopped acetylsalicylic acid, the median time to event was also 7 days from the time of acetylsalicylic acid cessation. If the thienopyridine was stopped but acetylsalicylic acid was maintained, the median time to event was 122 days. Among the 48 patients who stopped both agents, 36 cases (75%) occurred within 10 days. Among the 94 patients who discontinued a thienopyridine but continued acetylsalicylic acid, only 6 cases (6%) occurred within 10 days.. If acetylsalicylic acid therapy is maintained, short-term discontinuation of a thienopyridine may be relatively safe in patients with drug-eluting stents.

Topics: Aged; Aspirin; Case-Control Studies; Data Collection; Drug-Eluting Stents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; MEDLINE; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Thrombosis

One of the major classes of adenosine diphosphate (ADP) receptor antagonists are thienopyridines. Thienopyridines compose a subcategory of antiplatelet medications, known as ADP receptor inhibitors, used commonly for the treatment of atherosclerotic cardiovascular disease. Thienopyridines, including ticlopidine, clopidogrel and prasugrel, are prodrugs administered orally that are further metabolized by hepatocytes to create active metabolites that irreversibly bind ADP receptors located on the platelet membrane. Thus, these selected drugs have an inhibitory effect for the duration of the platelet's lifespan of 7-10 days. The goal of this manuscript is to review the currently available ADP receptor blockers with emphasis on chemical structure, mode of action and clinical use.

Topics: Cardiovascular Diseases; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Thrombosis

Platelets are critical modulators of atherothrombotic events. In the acute setting, platelets are activated and aggregate on the surface of atherosclerotic plaque that has ruptured, fissured, or developed erosions. The overlying thrombus leads to sudden development of arterial luminal obstruction, inducing ischemia and cellular necrosis. Inhibiting platelet reactivity is an important therapeutic goal in patients at risk for acute cardiovascular events. The thienopyridines are potent inhibitors of platelet aggregation and block the binding of adenosine 5'-diphosphate to purinergic receptors on the surface of the platelet membrane. The thienopyridine class includes ticlopidine, clopidogrel, and prasugrel. Clopidogrel is the most intensively studied. In recent years it has become apparent that approximately 20% to 25% of patients who would be expected to benefit from clopidogrel therapy are resistant to this drug, largely due to a polymorphism in the gene for cytochrome P450 2C19. The efficacy of clopidogrel can also be reduced if patients are receiving concomitant therapy with a proton pump inhibitor such as omeprazole. Prasugrel is a third-generation thienopyridine with faster time to onset and greater consistency in inhibiting platelet activity, and it has shown superiority to clopidogrel for reducing cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary interventions.

Topics: Hemorrhage; Humans; Prognosis; Pyridines; Risk Factors; Secondary Prevention; Thrombosis

Cilostazol has been associated with reduction in restenosis in patients undergoing coronary and peripheral arterial angioplasty. Our objective was to evaluate the impact of cilostazol on restenosis in patients undergoing contemporary PCI with bare metal (BMS) or drug eluting stents (DES) and treated with aspirin and thienopyridine.. Ten randomised trials (n=2,809 patients) comparing triple antiplatelet therapy (aspirin, thienopyridine and cilostazol) with standard dual antiplatelet therapy were included. Summary risk ratios for restenosis, late loss, target lesion revascularisation (TLR) and target vessel revascularisation (TVR) were calculated using fixed-effects models. Cilostazol was associated with a significant reduction in late loss in BMS (mean difference 0.24 mm, 95% CI 0.15-0.33, p<0.001) and DES groups (mean difference 0.12 mm, 95% CI 0.07-0.18, p<0.001). Cilostazol therapy was associated with a significant reduction in angiographic restenosis (Odds ratio [OR] 0.52, 95% CI 0.41- 0.66, p<0.001) with consistent benefits in patients treated with BMS (OR 0.49, 95% CI 0.35-0.70, p<0.001) or DES (OR 0.54, 95% CI 0.38-0.76, p=0.001). Addition of cilostazol to dual antiplatelet therapy was associated with a significant reduction in TLR (OR 0.38, 95% CI 0.25-0.58, p<0.001), with no difference in subacute stent thrombosis (OR 1.91, 95% CI 0.33-11.08, p=0.47), or major bleeding (OR 0.87, 95% CI 0.44-1.74, P=0.69) but with an increased risk of skin rash (OR 3.67, 95% CI 1.86-7.24, p<0.001).. Cilostazol in addition to dual antiplatelet therapy is associated with a reduction in angiographic restenosis in patients undergoing stent based PCI. This inexpensive drug may be particularly beneficial in patients who are at high risk of restenosis and it should undergo further evaluation in large, definitive randomised controlled trials.

Topics: Aged; Angioplasty, Balloon, Coronary; Aspirin; Cilostazol; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug Therapy, Combination; Drug-Eluting Stents; Exanthema; Female; Hemorrhage; Humans; Male; Metals; Middle Aged; Odds Ratio; Platelet Aggregation Inhibitors; Prosthesis Design; Publication Bias; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Stents; Tetrazoles; Thrombosis; Treatment Outcome

A common pathophysiological course in vascular diseases is an overwhelming activation and aggregation of blood platelets, which results in atherothrombosis. By causing the last decisive step of cerebral, coronary, or peripheral arterial ischemia thrombotic complications of atherosclerotic disease represent a major player in death cause statistics of most western countries. The development of novel therapies against platelet-dependent thrombosis and the concurrent improvement of existing therapeutic strategies thus is a paramount focus of pharmaceutical research. Currently, efficiency, dosing and indications of established antiplatelet substances are being re-evaluated, whilst new, so far unrecognized molecular targets for inhibition of platelet activity come up front. This not only allows for interesting new therapeutical options, but also widens our insight into the role platelets play in atherosclerosis in general. This article summarizes the relevant pathophysiology of platelet activation, presents current concepts in antiplatelet drug therapy, and highlights the role of platelets in vascular diseases apart from atherothrombosis.

Topics: Atherosclerosis; Clopidogrel; Drug-Eluting Stents; Humans; Piperazines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Thromboxane; Signal Transduction; Thiophenes; Thrombosis; Ticlopidine

Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure-related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Thrombosis

In most cases, arterial diseases are characterized by atherothrombosis causing organ or limb ischemia. Antithrombotic agents are a cornerstone in the therapeutic management of this pathology. Present approaches include anticoagulants and four types of antiplatelet drugs: aspirin, thienopyridines, dipyridamole and the anti-GPIIbIIIa molecules. Several questions are still pending, in particular concerning treatment tailoring according to clinical presentation and the duration of the antiplatelet treatment. This review focuses on the indications of the currently available antithrombotic agents in arterial diseases of atherothrombotic origin.

Topics: Abciximab; Antibodies, Monoclonal; Anticoagulants; Arteriosclerosis; Aspirin; Dipyridamole; Eptifibatide; Humans; Immunoglobulin Fab Fragments; Peptides; Platelet Aggregation Inhibitors; Pyridines; Thrombosis; Tirofiban; Treatment Outcome; Tyrosine

Recent years have witnessed significant advances in the percutaneous treatment of patients with atherosclerotic vascular disease. Anti-platelet and anti-thrombotic agents are routinely administered to minimize the risk of peri-procedural myonecrosis, stent thrombosis and other procedural complications. This article presents a current view of optimal adjunctive antithrombotic therapy for percutaneous coronary interventions (PCI), recognizing that optimal is a necessarily subjective label. This article focuses specifically on anticoagulant agents such as unfractionated heparin (UFH), the low-molecular weight heparins (LMWH), and direct thrombin inhibitors, and antiplatelet agents, such as aspirin, thienopyridines, and glycoprotein IIb/IIIa antagonists. It starts with a general discussion of anticoagulation and percutaneous intervention, followed by a summary of the modern-day view of the coagulation process. The mechanism of action of the individual agents is then presented, followed by some of the evidence base of recent clinical trials of anticoagulant and antiplatelet agents in PCI. Finally, we present summary recommendations for procedural anticoagulation in low risk, not-low risk, and high risk PCI, and list what we feel are appropriate doses for the agents employed. Ultimately, though, it is the individual interventional cardiologists who must decide for themselves exactly what constitutes optimal antithrombotic therapy for PCI.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Blood Coagulation; Clinical Trials as Topic; Clopidogrel; Heparin, Low-Molecular-Weight; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Stents; Thrombin; Thrombosis; Ticlopidine; Treatment Outcome

Adenosine diphosphate (ADP) and adenosine triphosphate (ATP) play a crucial role in hemostasis and thrombosis, and their receptors are potential targets for antithrombotic drugs. The ATP-gated channel P2X (1) and the two G protein-coupled P2Y (1) and P2Y (12) ADP receptors selectively contribute to platelet aggregation. Because of its central role in the formation and stabilization of a thrombus, the P2Y (12) receptor is a well-established target of antithrombotic drugs such as clopidogrel, which has proven efficacy in many clinical trials and experimental models of thrombosis. Competitive P2Y (12) antagonists have also been shown to be effective in experimental thrombosis as well as in several clinical trials. Studies in P2Y (1) and P2X (1) knockout mice and experimental thrombosis models using selective P2Y (1) and P2X (1) antagonists have shown that, depending on the conditions, these receptors could also be potential targets for new antithrombotic drugs. Because both P2X (1) and P2Y (1) receptor inhibition result in milder prolongation of the bleeding time as compared with P2Y (12) inhibition, the idea is put forward that combinations of P2 receptor antagonists could improve efficacy with diminished hemorrhagic risk. However, further studies with stronger and more selective P2 receptor antagonists are required to validate such a point of view.

Topics: Adenosine Diphosphate; Animals; Blood Vessels; Clinical Trials as Topic; Clopidogrel; Fibrinolytic Agents; Hemorrhagic Disorders; Humans; Membrane Proteins; Mice; Mice, Knockout; Platelet Aggregation Inhibitors; Pyridines; Receptors, Purinergic P2; Receptors, Purinergic P2X; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Thrombosis; Ticlopidine

Ticlopidine and clopidogrel belong to the same chemical family of thienopyridine adenosine diphosphate (ADP)-receptor antagonists. They have shown their efficacy as platelet antiaggregant and antithrombotic agents in many animal models, both ex vivo and in vivo. Although ticlopidine was discovered more than 30 years ago, it was only recently that the mechanism of action of ADP-receptor antagonists was characterized in detail. Ticlopidine and clopidogrel both behave in vivo as specific antagonists of P2Y (12), one of the ADP receptors on platelets. Metabolic steps that involve cytochrome P450-dependent pathways are required to generate the active metabolite responsible for this in vivo activity. The active moiety is a reactive thiol derivative that targets P2Y (12) on platelets. The interaction is irreversible, accounting for the observation that platelets are definitely antiaggregated, even if no active metabolite is detectable in plasma. The interaction is specific for P2Y (12); other purinoceptors such as P2Y (1) and P2Y (13) are spared. This results in inhibition of the binding of the P2Y (12) agonist 2-methylthio-ADP and the ADP-induced downregulation of adenylyl cyclase. Platelet aggregation is affected not only when triggered by ADP but also by aggregation inducers when used at concentrations requiring released ADP as an amplifier. The efficacy and safety of clopidogrel has been established in several large, randomized, controlled trials. The clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) trial demonstrated the superiority of clopidogrel over acetylsalicylic acid (ASA) in patients at risk of ischemic events, including ischemic stroke, myocardial infarction (MI), and peripheral arterial disease. The clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial showed a sustained, incremental benefit when clopidogrel was added to standard therapy (including ASA) in patients with unstable angina and non-Q-wave MI. The clopidogrel for the reduction of events during observation (CREDO) trial demonstrated the benefit of continuing clopidogrel (plus ASA) for 12 months, as opposed to 1 month, after percutaneous coronary intervention. The proven efficacy of clopidogrel, coupled with its favorable safety and tolerability profile, has prompted its evaluation in an extensive, ongoing clinical trial program that will help to further characterize the benefit of clopidogrel in patients with a range of atherothromboti

Topics: Adenosine Diphosphate; Animals; Arteriosclerosis; Aspirin; Clinical Trials as Topic; Clopidogrel; Cohort Studies; Double-Blind Method; Drug Resistance; Fibrinolytic Agents; Forecasting; Humans; Membrane Proteins; Meta-Analysis as Topic; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Randomized Controlled Trials as Topic; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thrombophilia; Thrombosis; Ticlopidine

CS-747 (prasugrel, LY640315) is a member of the thienopyridine class of oral platelet aggregation inhibitors that includes ticlopidine and clopidogrel. A single oral administration of CS-747 produced a dose-related inhibition of platelet aggregation in rats that was approximately 10- and 100-fold more potent than that of clopidogrel and ticlopidine, respectively. The antiaggregatory effect of CS-747 was evident at 30 minutes and lasted until 72 hours after dosing, indicating fast onset and long duration of action. CS-747 showed more potent antithrombotic activity compared with clopidogrel and ticlopidine with the same rank order as the antiaggregatory potencies. Combined administration of CS-747 with aspirin to rats produced substantially greater inhibition of both platelet aggregation and thrombus formation compared with each agent alone. The antiplatelet action of CS-747 is due to irreversible and selective blockade of platelet P2Y (12) adenosine diphosphate (ADP) receptors by its active metabolite R-138727. In phase I studies, a single oral dose of CS-747 (30 and 75 mg) produced > 50% inhibition of ADP-induced platelet aggregation, with rapid onset (1 hour) and long duration (> 48 hours) of action. In healthy volunteers, once-daily administration of 10 mg CS-747 for 10 days showed significant cumulative inhibition of platelet aggregation from 2 days after the first dose until at least 2 days after the final dose. Studies conducted to date indicate that CS-747 is a highly effective antiplatelet and antithrombotic agent and is anticipated to be effective in the treatment of atherothrombotic and other ischemic vascular diseases.

Topics: Adenosine Diphosphate; Adult; Animals; Aspirin; Biotransformation; Clinical Trials, Phase I as Topic; Clopidogrel; Collagen; Drug Evaluation, Preclinical; Drug Synergism; Fibrinolytic Agents; Hemostasis; Humans; Male; Membrane Proteins; Molecular Structure; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Thrombin; Thrombosis; Ticlopidine

An important role for adenosine diphosphate (ADP)-induced platelet activation and aggregation was proposed more than 40 years ago. The clinical use of clopidogrel, a prodrug of an irreversible P2Y (12) antagonist, has further proved the relevance of inhibiting signaling via the platelet-specific P2Y (12) ADP receptor in the prevention of cardiovascular events. Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration. In preclinical use, these compounds predictably and effectively inhibited platelet aggregation without significant increases in bleeding time. In clinical use, these compounds may have significant advantages over current antiplatelet agents. This article summarizes preclinical and clinical data on cangrelor and AZD6140 and discusses the potential of these compounds as novel antiplatelet therapies.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Administration, Oral; Animals; Arterial Occlusive Diseases; Clinical Trials as Topic; Dogs; Double-Blind Method; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents; Humans; Injections, Intravenous; Male; Membrane Proteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Rabbits; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor

The current standard of care for the treatment of arterial thrombosis includes anticoagulants and three classes of antiplatelet agents--aspirin, thienopyridines and glycoprotein IIb-IIIa antagonists. Although these drugs have had a significant impact on morbidity and mortality in several patient populations, up to 15% of the high risk patients with acute coronary syndrome continue to suffer from ischemic events. This problem may occur, in part, because the platelets in many patients are non-responsive to aspirin and clopidogrel. Murine models now indicate that platelets are not only responsible for arterial occlusion, they are also involved in the progression of atherosclerotic disease. New opportunities have emerged identifying potential targets and strategies for drug discovery suited to address these deficiencies by more effectively modulating platelet adhesion, thrombus growth, thrombus stability and the pro-inflammatory activity of platelets. In addition, a growing need has emerged for the development of bedside devices capable of bringing personalized medicine to patients being treated with antithrombotic drugs in order to measure the pharmacodynamic activities of new therapies, to assess the activities achieved by combined antithrombotic therapy, and to identify patients that fail to respond.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Atherosclerosis; Blood Platelets; Clopidogrel; Coronary Thrombosis; Disease Models, Animal; Disease Progression; Fibrinolytic Agents; Humans; Mice; Models, Biological; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Risk; Signal Transduction; Thrombosis; Ticlopidine; Time Factors

Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding.. To develop a clinical decision tool to identify patients expected to derive benefit vs harm from continuing thienopyridine beyond 1 year after PCI.. Among 11,648 randomized DAPT Study patients from 11 countries (August 2009-May 2014), a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. Validation was internal via bootstrap resampling and external among 8136 patients from 36 countries randomized in the PROTECT trial (June 2007-July 2014).. Twelve months of open-label thienopyridine plus aspirin, then randomized to 18 months of continued thienopyridine plus aspirin vs placebo plus aspirin.. Ischemia (myocardial infarction or stent thrombosis) and bleeding (moderate or severe) 12 to 30 months after PCI.. Among DAPT Study patients (derivation cohort; mean age, 61.3 years; women, 25.1%), ischemia occurred in 348 patients (3.0%) and bleeding in 215 (1.8%). Derivation cohort models predicting ischemia and bleeding had c statistics of 0.70 and 0.68, respectively. The prediction rule assigned 1 point each for myocardial infarction at presentation, prior myocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; -1 point for age 65 to younger than 75 years; and -2 points for age 75 years or older. Among the high score group (score ≥2, n = 5917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference [RD], -3.0% [95% CI, -4.1% to -2.0%], P < .001) compared with the low score group (score <2, n = 5731; 1.7% vs 2.3%; RD, -0.7% [95% CI, -1.4% to 0.09%], P = .07; interaction P < .001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4% [95% CI, -0.3% to 1.0%], P = .26) compared with the low score group (3.0% vs 1.4%; RD, 1.5% [95% CI, 0.8% to 2.3%], P < .001; interaction P = .02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding.. Among patients not sustaining major bleeding or ischemic events 1 year after PCI, a prediction rule assessing late ischemic and bleeding risks to inform dual antiplatelet therapy duration showed modest accuracy in derivation and validation cohorts. This rule requires further prospective evaluation to assess potential effects on patient care, as well as validation in other cohorts.. clinicaltrials.gov Identifier: NCT00977938.

Topics: Age Factors; Aged; Antineoplastic Agents, Phytogenic; Aspirin; Diabetes Mellitus; Drug-Eluting Stents; Female; Hemorrhage; Humans; Ischemia; Linear Models; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Risk Assessment; Risk Factors; Smoking; Thrombosis; Time Factors

The DAPT (Dual Antiplatelet Therapy) study enrolled patients after coronary stenting. Patients randomized to continued thienopyridine and aspirin after 12 months had lower ischemic risk but higher bleeding risk than those treated with placebo and aspirin.. This study sought to determine whether a decision tool (DAPT score) aids prescription of dual antiplatelet therapy duration in patients with or without prior myocardial infarction (MI) treated with coronary stents.. Patients were categorized according to any history of MI before the index procedure or no history of MI. Risk differences during the randomized treatment period (12 to 30 months) for ischemic (MI and/or stent thrombosis) and bleeding (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries moderate/severe) events were compared according to DAPT score.. Rates of MI were 3.8% versus 2.4% (p = 0.01) for patients with any MI versus no MI. Continued thienopyridine reduced late MI compared with placebo regardless of MI history (hazard ratio [HR] for any MI: 0.46; p < 0.001; HR for no MI: 0.60; p = 0.003) and increased bleeding (HR: 1.86, p = 0.01 any MI; HR: 1.58, p = 0.01 no MI). DAPT scores ≥2 were associated with reductions in MI/stent thrombosis with continued thienopyridine compared with placebo (2.7% vs. 6.0%, p < 0.001 any MI; 2.6% vs. 5.2%, p = 0.002 no MI), with comparable bleeding rates. Among patients with DAPT scores <2 in both groups, continued thienopyridine was associated with significantly increased bleeding but similar rates of ischemia.. Patients with previous MI have greater risk of late ischemic events than those with no MI history. The DAPT score improves prediction of patient benefit and harm from continued dual antiplatelet therapy beyond assessment of MI history alone. (The Dual Antiplatelet Therapy Study; NCT00977938).

Topics: Aspirin; Decision Support Techniques; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Risk Assessment; Secondary Prevention; Stents; Thrombosis

The benefits and risks of prolonged dual antiplatelet therapy may be different for patients with acute myocardial infarction (MI) compared with more stable presentations.. This study sought to assess the benefits and risks of 30 versus 12 months of dual antiplatelet therapy among patients undergoing coronary stent implantation with and without MI.. The Dual Antiplatelet Therapy Study, a randomized double-blind, placebo-controlled trial, compared 30 versus 12 months of dual antiplatelet therapy after coronary stenting. The effect of continued thienopyridine on ischemic and bleeding events among patients initially presenting with versus without MI was assessed. The coprimary endpoints were definite or probable stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) moderate or severe bleeding.. Of 11,648 randomized patients (9,961 treated with drug-eluting stents, 1,687 with bare-metal stents), 30.7% presented with MI. Between 12 and 30 months, continued thienopyridine reduced stent thrombosis compared with placebo in patients with and without MI at presentation (MI group, 0.5% vs. 1.9%, p < 0.001; no MI group, 0.4% vs. 1.1%, p < 0.001; interaction p = 0.69). The reduction in MACCE for continued thienopyridine was greater for patients with MI (3.9% vs. 6.8%; p < 0.001) compared with those with no MI (4.4% vs. 5.3%; p = 0.08; interaction p = 0.03). In both groups, continued thienopyridine reduced MI (2.2% vs. 5.2%, p < 0.001 for MI; 2.1% vs. 3.5%, p < 0.001 for no MI; interaction p = 0.15) but increased bleeding (1.9% vs. 0.8%, p = 0.005 for MI; 2.6% vs. 1.7%, p = 0.007 for no MI; interaction p = 0.21).. Compared with 12 months of therapy, 30 months of dual antiplatelet therapy reduced the risk of stent thrombosis and MI in patients with and without MI, and increased bleeding. (The Dual Antiplatelet Therapy Study [The DAPT Study]; NCT00977938).

Topics: Aspirin; Double-Blind Method; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Pyridines; Risk Assessment; Stents; Thrombosis; Time Factors

The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial.. Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis.. The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months.. Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014).. Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Topics: Acute Coronary Syndrome; Aged; Aspirin; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Morpholines; Platelet Aggregation Inhibitors; Pyridines; Rivaroxaban; Stents; Thiophenes; Thrombosis; Treatment Outcome

Cilostazol has been associated with reduction in restenosis in patients undergoing coronary and peripheral arterial angioplasty. Our objective was to evaluate the impact of cilostazol on restenosis in patients undergoing contemporary PCI with bare metal (BMS) or drug eluting stents (DES) and treated with aspirin and thienopyridine.. Ten randomised trials (n=2,809 patients) comparing triple antiplatelet therapy (aspirin, thienopyridine and cilostazol) with standard dual antiplatelet therapy were included. Summary risk ratios for restenosis, late loss, target lesion revascularisation (TLR) and target vessel revascularisation (TVR) were calculated using fixed-effects models. Cilostazol was associated with a significant reduction in late loss in BMS (mean difference 0.24 mm, 95% CI 0.15-0.33, p<0.001) and DES groups (mean difference 0.12 mm, 95% CI 0.07-0.18, p<0.001). Cilostazol therapy was associated with a significant reduction in angiographic restenosis (Odds ratio [OR] 0.52, 95% CI 0.41- 0.66, p<0.001) with consistent benefits in patients treated with BMS (OR 0.49, 95% CI 0.35-0.70, p<0.001) or DES (OR 0.54, 95% CI 0.38-0.76, p=0.001). Addition of cilostazol to dual antiplatelet therapy was associated with a significant reduction in TLR (OR 0.38, 95% CI 0.25-0.58, p<0.001), with no difference in subacute stent thrombosis (OR 1.91, 95% CI 0.33-11.08, p=0.47), or major bleeding (OR 0.87, 95% CI 0.44-1.74, P=0.69) but with an increased risk of skin rash (OR 3.67, 95% CI 1.86-7.24, p<0.001).. Cilostazol in addition to dual antiplatelet therapy is associated with a reduction in angiographic restenosis in patients undergoing stent based PCI. This inexpensive drug may be particularly beneficial in patients who are at high risk of restenosis and it should undergo further evaluation in large, definitive randomised controlled trials.

Topics: Aged; Angioplasty, Balloon, Coronary; Aspirin; Cilostazol; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug Therapy, Combination; Drug-Eluting Stents; Exanthema; Female; Hemorrhage; Humans; Male; Metals; Middle Aged; Odds Ratio; Platelet Aggregation Inhibitors; Prosthesis Design; Publication Bias; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Stents; Tetrazoles; Thrombosis; Treatment Outcome

Stent fracture (SF) and peri-stent contrast staining (PSS) after sirolimus-eluting stent (SES) implantation are considered to be related to very late stent thrombosis (VLST). How dual antiplatelet therapy (DAPT) beyond 1 year affects the clinical outcomes of patients with SF or PSS remains unclear.Methods and Results:Based on their DAPT status, 1,962 patients undergoing SES implantation were classified as on-thienopyridine (n=1,404) or off-thienopyridine (n=558). The 6-year incidence of VLST was significantly lower in the on-thienopyridine patients (0.56% vs. 1.8%, P=0.01), whereas cardiac death and myocardial infarction (MI) were similar (5.0% vs. 6.2%, P=0.31; 3.2% vs. 4.0%, P=0.33; respectively). The 1,962 patients were also classified as having SF/PSS (n=256) or non-SF/PSS (n=1,706). In the SF/PSS group, VLST and MI were significantly lower in on-thienopyridine patients (1.9% vs. 10.1%, P=0.003; 3.5% vs. 10.3%, P=0.02; respectively). In the non-SF/PSS group, VLST and MI were similar (0.36% vs. 0.45%, P=0.78; 3.2% vs. 3.0%, P=0.93; respectively). In both groups, cardiac death was similar (3.6% vs. 4.3%, P=0.78; 5.2% vs. 6.5%, P=0.32; respectively).. Prolonged DAPT was associated with significantly lower incidences of VLST and MI in the SF/PSS group, but had no effect on cardiac death, VLST, or MI in the non-SF/PSS group.

Topics: Aged; Aspirin; Death; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Prosthesis Implantation; Pyridines; Retrospective Studies; Sirolimus; Staining and Labeling; Thrombosis; Time Factors; Treatment Outcome

Healthcare providers often are faced with the challenge of determining an appropriate length of dual antiplatelet therapy (DAPT) for patients who have had percutaneous coronary intervention and stent placement. This is an especially challenging clinical decision for patients with drug-eluting stents, as several studies show different results when assessing risk and benefit.

Topics: Aspirin; Drug Therapy, Combination; Drug-Eluting Stents; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Postoperative Period; Pyridines; Risk Assessment; Risk Factors; Thrombosis; Time 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

The present study examined the effects of prasugrel in a mouse model of thrombosis-induced neointimal hyperplasia. Following carotid artery injury by application of ferric chloride solution, thrombus formation was assessed on Day 1 and neointimal thickening was assessed on Day 21. Single administrations of prasugrel at 0.3-3mg/kg (p.o.) resulted in a dose-related and sustained inhibition of ADP-induced platelet aggregation through 24h. Single and multiple (1 and 3 weeks) administration of prasugrel (3mg/kg loading and 1mg/kg/day maintenance doses) resulted in a marked inhibition of neointimal thickening in the injured artery. In the dose-response study, a single administration of prasugrel at 0.3-3mg/kg (p.o.) dose-relatedly inhibited thrombus formation and neointimal thickening on Days 1 and 21, respectively. The degree of neointimal hyperplasia in the injured artery correlated significantly with the thrombus indices, time to occlusion and patency rate. To explore possible mechanisms of inhibition of neointimal hyperplasia by prasugrel, mRNA expression levels of inflammatory and fibrosis markers were determined in injured arteries. Prasugrel treatment resulted in reduced MCP-1, ICAM-1 and TGF-β mRNA levels on Day 2 (24h after the injury) and Day 8 (1 week after the injury) in the target arteries. In conclusion, we found that a single oral loading dose of prasugrel markedly prevented neointimal hyperplasia by inhibiting platelet activation and thrombus formation and was associated with inhibition of the expression of inflammatory and fibrosis markers, including MCP-1, ICAM-1 and TGF-β, in the injured arteries.

Topics: Adenosine Diphosphate; Animals; Aorta; Arterial Occlusive Diseases; Arteries; Carotid Arteries; Chemokine CCL2; Chlorides; Ferric Compounds; Hyperplasia; Inflammation; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Neointima; Platelet Aggregation; Prasugrel Hydrochloride; Pyridines; RNA, Messenger; Thrombosis; Time Factors; Transforming Growth Factor beta1

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

The influences of antiplatelet therapy discontinuation on the risk of stent thrombosis and long-term clinical outcomes after drug-eluting stent implantation have not yet been addressed adequately.. In an observational study in Japan, 2-year outcomes were assessed in 10 778 patients undergoing sirolimus-eluting stent implantation. Data on status of antiplatelet therapy during follow-up were collected prospectively. Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years. Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of stent thrombosis than those who continued both in the intervals of 31 to 180 days, 181 to 365 days, and 366 to 548 days after stent implantation (1.76% versus 0.1%, P<0.001; 0.72% versus 0.07%, P=0.02; and 2.1% versus 0.14%, P=0.004, respectively). When discontinuation of aspirin was taken into account, patients who discontinued thienopyridine only did not have an excess of stent thrombosis in any of the time intervals studied. Adjusted rates of death or myocardial infarction at 24 months were 4.1% for patients taking thienopyridine and 4.1% for patients not taking thienopyridine (P=0.99) in the 6-month landmark analysis.. Discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis. Landmark analysis did not suggest an apparent clinical benefit of thienopyridine use beyond 6 months after sirolimus-eluting stent implantation.

Topics: Aged; Aged, 80 and over; Drug-Eluting Stents; Electrocardiography; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Sirolimus; Thrombosis

Topics: Angioplasty, Balloon, Coronary; Clopidogrel; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Humans; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Pyridines; Stents; Thrombosis; Ticlopidine

Ticagrelor (AZD6140), the first reversibly binding oral P2Y(12) receptor antagonist, blocks adenosine diphosphate (ADP)-induced platelet aggregation via a mode of action distinct from that of thienopyridine antiplatelet agents. The latter must be metabolically activated and binds irreversibly to P2Y(12) for the life of the platelet, precluding restoration of hemostatic function without the generation of new platelets. In in vitro studies comparing binding characteristics of ticagrelor and compound 105, a chemical compound indistinguishable from the active metabolite of prasugrel, ticagrelor exhibited 1) an approximately 100-fold higher affinity for P2Y(12) and rapid achievement of equilibrium (vs no equilibrium reached with compound 105) as assessed by radioligand displacement in a receptor filtration binding assay, 2) 48-fold greater potency in a functional receptor assay using recombinant human P2Y(12), and 3) 63-fold greater potency in inhibiting ADP-induced aggregation in washed human platelets. In rat and dog models of thrombosis/hemostasis, there was greater separation between doses that provided antithrombotic effect and those that increased bleeding for ticagrelor compared with clopidogrel and compound 072, a chemical compound indistinguishable from the prasugrel parent compound. The ratio of dose resulting in 3-fold increase in bleeding time to dose resulting in 50% restoration of blood flow in rats was 9.7 for ticagrelor compared with 2.0 for clopidogrel and 1.4 for compound 072. Similar results were observed in dogs. Our findings suggest that reversibility of P2Y(12) binding with ticagrelor may account for the greater separation between antithrombotic effects and increased bleeding compared with the irreversible binding of clopidogrel and prasugrel.

Topics: Adenosine; Animals; CHO Cells; Clopidogrel; Cricetinae; Cricetulus; Disease Models, Animal; Dogs; Hemostasis; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine; Transfection

Topics: Angioplasty, Balloon, Coronary; Drug Therapy, Combination; Humans; Patient Selection; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Pyridines; Risk Assessment; Stents; Thrombosis; Treatment Outcome

The need for prolonged aspirin and thienopyridine therapy and the risk of stent thrombosis (ST) remain as drawbacks associated with drug-eluting stents.. A prospective observational cohort study was conducted between June 2002 and January 2004 on 3021 patients consecutively and successfully treated in 5389 lesions with drug-eluting stents. Detailed patient information was collected on antiplatelet therapy. We analyzed the incidence of ST throughout the 18-month follow-up period and its relationship with thienopyridine therapy. ST occurred in 58 patients (1.9%) at 18 months. Forty-two patients (1.4%) experienced the event within 6 months of stent implantation. Acute myocardial infarction (fatal or nonfatal) occurred in 46 patients (79%) and death in 23 patients (39%) with ST. The median interval from discontinuation of thienopyridine therapy to ST was 13.5 days (interquartile range 5.2 to 25.7 days) for the first 6 months and 90 days (interquartile range 30 to 365 days) between 6 and 18 months. On multivariable analysis, the strongest predictor for ST within 6 months of stenting was discontinuation of thienopyridine therapy (hazard ratio, 13.74; 95% CI, 4.04 to 46.68; P<0.001). Thienopyridine discontinuation after 6 months did not predict the occurrence of ST (hazard ratio, 0.94; 95% CI, 0.30 to 2.98; P=0.92).. Discontinuation of thienopyridine therapy was the major determinant of ST within the first 6 months, but insufficient information is available to determine whether there is benefit in continuing a thienopyridine beyond 6 months.

Topics: Aged; Aspirin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Paclitaxel; Platelet Aggregation Inhibitors; Pyridines; Sirolimus; Stents; Thrombosis; Treatment Outcome

Topics: Contraindications; Drug Delivery Systems; Humans; Meta-Analysis as Topic; Pyridines; Stents; Thrombosis; United States

Topics: Algorithms; Aspirin; Clopidogrel; Drug Therapy, Combination; Humans; Incidence; Paclitaxel; Platelet Aggregation Inhibitors; Pyridines; Sirolimus; Stents; Survivors; Thrombosis; Ticlopidine

Although drug-eluting stents (DES) significantly reduce restenosis, they require 3 to 6 months of thienopyridine therapy to prevent stent thrombosis. The rate and consequences of prematurely discontinuing thienopyridine therapy after DES placement for acute myocardial infarction (MI) are unknown.. We used prospectively collected data from a 19-center study of MI patients to examine the prevalence and predictors of thienopyridine discontinuation 30 days after DES treatment. We then compared the mortality and cardiac hospitalization rates for the next 11 months between those who stopped and those who continued thienopyridine therapy. Among 500 DES-treated MI patients who were discharged on thienopyridine therapy, 68 (13.6%) stopped therapy within 30 days. Those who stopped were older, less likely to have completed high school or be married, more likely to avoid health care because of cost, and more likely to have had preexisting cardiovascular disease or anemia at presentation. They were also less likely to have received discharge instructions about their medications or a cardiac rehabilitation referral. Patients who stopped thienopyridine therapy by 30 days were more likely to die during the next 11 months (7.5% versus 0.7%, P<0.0001; adjusted hazard ratio=9.0; 95% confidence interval=1.3 to 60.6) and to be rehospitalized (23% versus 14%, P=0.08; adjusted hazard ratio=1.5; 95% confidence interval=0.78 to 3.0).. Almost 1 in 7 MI patients who received a DES were no longer taking thienopyridines by 30 days. Prematurely stopping thienopyridine therapy was strongly associated with subsequent mortality. Strategies to improve the use of thienopyridines are needed to optimize the outcomes of MI patients treated with DES.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cause of Death; Clopidogrel; Combined Modality Therapy; Coronary Restenosis; Drug Administration Schedule; Drug Implants; Female; Follow-Up Studies; Hospitalization; Humans; Life Tables; Male; Middle Aged; Mortality; Myocardial Infarction; Patient Education as Topic; Platelet Aggregation Inhibitors; Prevalence; Proportional Hazards Models; Prospective Studies; Pyridines; Registries; Sirolimus; Stents; Survival Analysis; Thrombosis; Ticlopidine; Treatment Outcome; Treatment Refusal

Topics: Angioplasty, Balloon, Coronary; Clopidogrel; Coronary Restenosis; Coronary Stenosis; Humans; Paclitaxel; Platelet Aggregation Inhibitors; Pyridines; Stents; Thrombosis; Ticlopidine