Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Combination antiplatelet agents, particularly aspirin and ticlopidine, have found increased use in the prevention of arterial thrombosis. Clopidogrel, a thienopyridine derivative, like ticlopidine was recently approved by the U.S. Food and Drug Administration (FDA) for the reduction of ischemic events in patients with myocardial infarction, stroke, or peripheral arterial disease and appears to have much less hematologic toxicity than ticlopidine has. Thrombosis of hemodialysis access grafts is a major cause of morbidity in this patient population. Combination antiplatelet agents may be particularly useful in the prevention of hemodialysis access graft thrombosis. In preparation for such a study, we have performed a pharmacodynamic study of the platelet inhibitory effects of clopidogrel in patients on maintenance hemodialysis. Nine chronic hemodialysis patients were studied. Baseline platelet aggregation studies were performed, after which the subjects were begun on clopidogrel 75 mg daily. Platelet aggregation studies were repeated after 14 days of therapy. Drug was stopped and a final set of platelet aggregation studies were performed 7 days later. Because clopidogrel acts by inhibiting adenosine diphosphate (ADP)-induced platelet aggregation, we used ADP as the agonist in the platelet aggregation studies. We also measured the time required to achieve hemostasis after removing the dialysis needles at the termination of a dialysis session. Patients were carefully monitored for any adverse reaction to clopidogrel. Fourteen days' treatment with clopidogrel inhibited ADP-induced platelet aggregation from 48 to 23% with ADP 2 microM (P=0.0113), from 59 to 38% with ADP 5 microM (P=0. 0166), and from 66 to 44% with ADP 10 microM (P=0. 0172). This inhibition of platelet aggregation was reversed 7 days after stopping clopidogrel. Clopidogrel administration did not affect the time required to achieve hemostasis after removal of the dialysis needles. No adverse reactions were noted. No patient had evidence of bleeding, rash or gastro-intestinal (GI) upset. Clopidogrel inhibits ADP-induced platelet aggregation in subjects receiving chronic maintenance hemodialysis. The magnitude of inhibition is similar to that reported in nonuremic subjects with atherosclerosis. This inhibition is reversible within 7 days of discontinuing the drug. No adverse reactions to the drug were noted in this short-term (14-day) trial.
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PMID:A pharmacodynamic study of clopidogrel in chronic hemodialysis patients. 1100 34

Atherosclerosis involves structural change to the intima and media of medium- and large-sized arteries. Although an atherosclerotic plaque may remain clinically silent, it is prone to disruption, leading to local platelet activation and aggregation. Therefore, the major complication of atherosclerosis is thrombosis, with local occlusion or distal embolism - a generalized disease process known as atherothrombosis. The three main clinical manifestations of atherothrombosis are coronary heart disease (myocardial infarction and angina), peripheral arterial disease and cerebral ischaemia. Atherothrombosis is a leading cause of mortality, and stroke is the leading cause of disability in adults, the second most important cause of dementia and the third most common cause of death in Western countries. Ischaemic stroke accounts for 80% of strokes and atherothrombosis accounts for approximately 20% of all strokes. Criteria for atherothrombotic stroke are evidence of a 50% (or greater) stenosis of a cervical artery and exclusion of other potential causes. The incidence of cerebrovascular events is 2,900 per million inhabitants per year, consisting of 500 transient ischaemic attacks and 2,400 strokes, of which 75% are first-ever stroke. The prevalence of stroke in the same population is 12,000, of which 800 patients (7%) per year have recurrences. The risk of ipsilateral stroke is 5% per year and the risk of a cardiac event is higher at 7%. Besides optimal management of risk factors for atherothrombosis and carotid surgery, antiplatelet therapy is the cornerstone of vascular prevention. In secondary prevention, antiplatelet agents are effective in reducing the risk of further ischaemic events in patients with atherothrombosis. Clopidogrel, a newly licensed ADP receptor antagonist, is the only antiplatelet agent to have demonstrated its superiority versus aspirin for the reduction of major ischaemic events (myocardial infarction, ischaemic stroke, vascular death) in patients whose initial manifestation of atherothrombosis was one of the three main clinical manifestations of the disease (recent ischaemic stroke, myocardial infarction, established peripheral arterial disease).
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PMID:Atherothrombosis: a major health burden. 1131 15

In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, clopidogrel showed a statistically significant superiority over aspirin in the prevention of ischaemic stroke, myocardial infarction and vascular death in patients with symptomatic atherosclerosis. More recently, post-hoc analysis of the data also showed that repeat hospitalization for ischaemic or bleeding events was decreased with clopidogrel compared with aspirin. Complementary analyses show that the benefit of clopidogrel over aspirin is amplified in a large population at very high risk of further atherothrombotic events (diabetics, patients with high cholesterol, and patients with previous manifestations of atherothrombosis). A potential clinically useful advantage of clopidogrel is its low propensity for adverse interaction with angiotensin-converting enzyme (ACE) inhibitors, contrary to what may be seen with aspirin, as observed in a post-hoc CAPRIE analysis. The putative aspirin-ACE inhibitor interaction is being tested prospectively in the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial - a randomized comparison of warfarin, clopidogrel and aspirin in patients with chronic heart failure. The good gastrointestinal tolerance of clopidogrel seen in CAPRIE has been further demonstrated in a study in healthy volunteers where there was a markedly lower gastroduodenal erosion score after 8 days' administration of clopidogrel 75 mg/day compared with aspirin 325 mg/day (p < 0.001). Following the positive findings obtained with clopidogrel plus aspirin in the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) trial, other studies of clopidogrel plus aspirin have been initiated or are planned. These include Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH), a randomized comparison of clopidogrel plus aspirin versus clopidogrel in high-risk patients with recent stroke or transient ischaemic attack.
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PMID:Benefit of ADP receptor antagonists in atherothrombotic patients: new evidence. 1131 16

Aspirin inhibits platelet activation by irreversibly inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of serious vascular events (stroke, myocardial infarction or vascular death) by about one quarter in a range of patients with symptomatic atherosclerosis at high risk of a subsequent event. The adenosine diphosphate (ADP) receptor antagonists clopidogrel and ticlopidine are significantly more effective than aspirin in high-risk vascular patients, further reducing the odds of serious vascular events by about 10% (95% CI 2-19%) over the benefit provided by aspirin. The ADP receptor antagonists are also associated with a significant 30% reduction in the odds of gastrointestinal haemorrhage (odds ratio 0.71, 95% CI 0.59-0.86). Ticlopidine increases the odds of skin rash and of diarrhoea by more than twofold compared with aspirin, whereas clopidogrel is associated with a one-third increase in the odds of rash and of diarrhoea. Only ticlopidine increases the odds of neutropenia compared with aspirin. There is no clear evidence as yet for the benefit of dipyridamole or an oral GP IIb/IIIa receptor antagonist as single antiplatelet agents in atherothrombotic patients. Amongst high vascular risk patients, the combination of low-dose aspirin and high-dose dipyridamole is associated with about a 10% (95% CI 0-20%) reduction in the odds of a serious vascular event. Most of this reduction is due to a 23% reduction in non-fatal stroke. The size of this estimate continues to be investigated in an ongoing study of patients with transient ischaemic attack and stroke. The combined use of aspirin and ticlopidine is markedly superior to heparin, warfarin and aspirin for reducing thrombotic complications after coronary artery stenting. Clopidogrel plus aspirin has been shown to be safer than aspirin and ticlopidine in coronary stenting, and is now under long-term evaluation in unstable angina, and other conditions in which patients are at high risk of atherothrombotic events.
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PMID:Current oral antiplatelet agents to prevent atherothrombosis. 1131 17

Clopidogrel is launched in Belgium by Sanofi-Synthelabo and Bristol-Myers Squibb under the trade name of Plavix. It is a potent and irreversible ADP receptor antagonist that proved to be more effective than aspirin as antiplatelet agent in the multicentre, randomised double-blind CAPRIE study. It is indicated, at a dosage of 75 mg/day, for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease. Furthermore, recent studies demonstrated that the combination of clopidogrel with aspirin is more effective than aspirin alone and better tolerated than the combination ticlopidine-aspirin for the prevention of atherothrombosis after placement of intravascular stents. Ongoing trials are evaluating the efficacy and safety of such clopidogrel-aspirin combination after acute ischaemic coronary events or in patients at very high risk of stroke. Thus the indications of clopidogrel may become even larger in a next future.
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PMID:[Pharmacy clinics. Medication of the month. Clopidogrel (Plavix)]. 1133 92

The usefulness of Clopidogrel as inhibitor of platelet aggregation has been demonstrated, but its effect on hemoreological parameters, such as whole blood viscosity at low and high shear rate, red cell aggregation and deformability indexes, filterability rate and and deformability of red blood cells has not been studied. This study revealed that, in subjects with impaired blood rheology and ultrasound evidence of atherosclerosis, 3-weeks treatment with clopidogrel (75 mg daily) improved blood viscosity at high shear rate and other hemorheological parameters, including red cell filterability rates and dynamic red cell deformability index (p<0.01 for all), without any unwanted side effect. Blood viscosity at low shear rate and red cell aggregation index improved after only 1-week treatment, and the reductions were mantained after two and three weeks (p<0.01). These results indicate that, similarly to another thienopyridine such as ticlopidine, Clopidogrel may have a positive influence on several hemorheological parameters, thus exerting its protection not only through inhibition of platelet function, but also through changes in the hemorheological profile.
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PMID:Clopidogrel: hemorheological effects in subjects with subclinical atherosclerosis. 1179 Aug 68

Patients with a clinical manifestation of atherothrombosis such as a recent ischaemic cerebrovascular event are at high risk of subsequent events. Atherothrombosis often reflects disseminated disease; thus, further events may occur not only in the same arterial distribution but also in other vascular beds. To achieve adequate secondary prevention in these patients, long-term antiplatelet therapy with consistent benefit across the atherothrombosis spectrum is required. In the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) Trial, clopidogrel (clopidogrel bisulphate) was superior to acetylsalicylic acid (ASA) in reducing the combined risk of ischaemic stroke (IS), myocardial infarction (MI) or vascular death in patients with symptomatic atherosclerosis. Post hoc analyses demonstrated that the benefit of clopidogrel was amplified in high-risk patients, including patients with a history of previous ischaemic events, diabetic patients and patients with hypercholesterolaemia. The synergistic antiplatelet effect produced by using clopidogrel on top of ASA may be beneficial in high-risk patients. The benefit of dual antiplatelet therapy was recently examined in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) Study, which demonstrated that long-term treatment with clopidogrel on top of standard therapy including ASA was superior to standard therapy alone in the prevention of major vascular ischaemic events in patients with unstable angina or non-Q-wave MI. The ongoing MATCH (Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent Transient Ischaemic Attack or Ischaemic Stroke) trial will evaluate the efficacy and safety of clopidogrel plus ASA versus clopidogrel alone in patients with recent transient ischaemic attack (TIA) or IS and with at least one additional risk factor. Approximately 7,600 patients will be enroled, with treatment and follow-up for each patient lasting 18 months. The primary combined efficacy endpoint will be the first occurrence of an event in the composite of IS, MI, vascular death or rehospitalization for an acute ischaemic event during the follow-up period. MATCH will explore the potential benefit of clopidogrel in high-risk stroke/TIA patients and together with CAPRIE and CURE could provide further evidence of the long-term benefit of clopidogrel in patients with major atherothrombotic manifestations.
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PMID:From CURE to MATCH: ADP receptor antagonists as the treatment of choice for high-risk atherothrombotic patients. 1180 84

The peripheral vascular system makes up the largest single "organ system" and holds many biological secrets that, when unlocked, can open doors for new treatments for all vascular beds, including those of the coronary and cerebral arteries. The coronary and noncoronary circulations are inseparable and interdependent. Cardiologists as well as primary care physicians should have a global view in the management of patients with PAD. The treatment of atherosclerosis in any of the arterial beds is a multifactorial problem. PAD is underrecognized. Antiplatelet and lipid-lowering therapy is underutilized in patients with PAD. Clopidogrel, an antiplatelet drug, has proven to prevent adverse cardiovascular events in patients with PAD. Therapeutic angiogenesis has been reported to improve severe claudication.
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PMID:Peripheral arterial disease is only the tip of the atherosclerotic "iceberg". 1210 40

Antiplatelet drugs have been shown to prevent a range of atherothrombotic events, including transient ischaemic attack (TIA) and ischaemic stroke. Clopidogrel and ticlopidine are adenosine diphosphate (ADP)-receptor antagonists that inhibit ADP-induced fibrinogen binding to platelets, a necessary step in the platelet aggregation process. The Antithrombotic Trialists' Collaboration recently published a major meta-analysis that assessed the effect of antiplatelet therapy in patients with various manifestations of atherosclerosis. In total, this analysis included 135,000 patients in comparisons of antiplatelet agents versus control and 77,000 patients in comparisons of different antiplatelet regimens. This meta-analysis found that overall, antiplatelet therapy reduces the combined odds of stroke, myocardial infarction (MI) or vascular death by 22%, and that antiplatelet agents reduce the odds of a non-fatal stroke by 25% over a wide range of patients with or without a history of cerebrovascular disease. In the CAPRIE trial of clopidogrel versus acetylsalicylic acid (ASA), there was a 10% odds reduction for stroke, MI or vascular death in favour of clopidogrel (p = 0.03). In a meta-analysis performed by the Cochrane Stroke Group, ADP-receptor antagonist therapy significantly reduced the odds of a serious vascular event (stroke, MI or vascular death) by 9% (2p = 0.01) and of any stroke by 12%. The safety/tolerability profile of clopidogrel was superior to that of ticlopidine, and at least as good as that of ASA. In CURE, a long-term benefit was observed with the use of clopidogrel on top of standard therapy (including ASA in all patients), with a 20% relative risk reduction for the primary endpoint of cardiovascular death, MI or stroke (p < 0.001) in patients with unstable angina and non-Q-wave MI. A consistent benefit was seen across all patient subgroups, including patients with a previous history of stroke. More recently, CREDO has demonstrated the incremental benefit of prolonged use of clopidogrel on top of ASA in patients undergoing elective PCI, with a 27% reduction in the combined risk of death, MI or stroke after 12 months of therapy (p = 0.02) and a 25% reduction in stroke over the same time period. The MATCH trial is currently being conducted to test the hypothesis that long-term administration of clopidogrel on top of ASA is superior to clopidogrel alone for the reduction of major ischaemic events in patients with recent TIA or ischaemic stroke who are at high risk of atherothrombotic recurrence. Further trials of clopidogrel on top of standard therapy (including ASA) are planned in neurology; these include SPS3, in patients with small subcortical strokes, and ATARI, in patients who have recently recovered from a TIA.
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PMID:Evidence with antiplatelet therapy and ADP-receptor antagonists. 1269 15

Platelet inhibiting drugs are mainly used to prevent arterial thrombosis complicating atherosclerosis. Numerous clinical trials have delineated their clinical indications and precise guidelines are internationally available. The mechanism of action of aspirin is well understood: inhibition of platelet synthesis of thromboxane, and there is a pretty good relationship between pharmacology at the molecular and cellular levels and clinical results. The recently available drugs are the following. Clopidogrel is a thienopyridine, which irreversibly inhibits platelet activation by ADP interacting with the recently cloned P2Y12 receptor. There are also inhibitors of the fibrinogen binding to its platelet receptor, the glycoprotein IIb/IIIa complex, which is the key mechanism of platelet aggregation. These new drugs are widely used in patients with active coronary artery disease, on top of aspirin.
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PMID:[Platelet inhibitors: old and new]. 1269 52


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