Ticlopidine hydrochloride use and threatened stroke.

Ticlopidine hydrochloride is an antiplatelet agent of proven antithrombotic efficacy that in December 1991 became available for general clinical use in the United States. The relative value of ticlopidine compared with aspirin, also an effective antiplatelet agent, has become a key clinical issue. Whereas ticlopidine is somewhat more effective than aspirin for preventing stroke in certain populations, it is also more expensive and potentially toxic. We recommend its use for patients with threatened stroke who are intolerant of aspirin and for patients who have cerebral ischemic symptoms despite aspirin therapy. Patients surviving major ischemic stroke make up a third group for whom ticlopidine use may be recommended in preference to aspirin. The use of ticlopidine rather than aspirin in patients with other cerebrovascular conditions is not strongly supported by existing data. The risk-benefit-cost equation involving ticlopidine versus other antithrombotic therapies is complex, rendering a wide range of acceptable management practices. If reliable laboratory monitoring for neutropenia during the first 3 months of therapy is not feasible, ticlopidine should not be used.     

Thrombelastographic haemostatic status and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): assessing and monitoring the antithrombotic effect of clopidogrel and aspirin versus aspirin alone in hypercoagulable patients: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Hypercoagulability, assessed by the thrombelastography (TEG) assay, has in several observational studies been associated with an increased risk of post-procedural thromboembolic complications. We hypothesize that intensified antiplatelet therapy with clopidogrel and aspirin, as compared to aspirin alone, will improve saphenous vein graft patency in preoperatively TEG-Hypercoagulable coronary artery bypass surgery (CABG) patients and reduce their risk for thromboembolic complications and death postoperatively. METHODS: This is a prospective randomized clinical trial, with an open-label design with blinded evaluation of graft patency. TEG-Hypercoagulability is defined as a TEG maximum amplitude above 69 mm. Two hundred and fifty TEG-Hypercoagulable patients will be randomized to either an interventional group receiving clopidogrel 75 mg daily for three months (after initial oral bolus of 300 mg) together with aspirin 75 mg or a control group receiving aspirin 75 mg daily alone. Monitoring of antiplatelet efficacy and on-treatment platelet reactivity to clopidogrel and aspirin will be conducted with Multiplate aggregometry. Graft patency will be assessed with Multislice computed tomography (MSCT) at three months after surgery. CONCLUSIONS: The present trial is the first randomized clinical trial to evaluate whether TEG-Hypercoagulable CABG patients will benefit from intensified antiplatelet therapy after surgery. Monitoring of platelet inhibition from instituted antithrombotic therapy will elucidate platelet resistance patterns after CABG surgery. The results could be helpful in redefining how clinicians can evaluate patients preoperatively for their postoperative thromboembolic risk and tailor individualized postoperative antiplatelet therapy. Trial registration Clinicaltrials.gov Identifier NCT01046942.     

Debate: PCI vs CABG: a moving target, but we are gaining

The treatment of patients with coronary artery disease continues to evolve; all three strategies – medical therapy, surgical revascularization, and percutaneous coronary intervention – have changed. Medical therapy with intense risk-factor modification and treatment with a statin, aspirin, and angiotensin-converting enzyme (ACE) inhibitors, should be used unless contraindicated. Surgical therapy has also changed with the introduction of minimally invasive, beating heart surgery. Percutaneous coronary intervention has perhaps changed the most radically with adjunctive therapy – glycoprotein IIb/IIIa inhibitors, thienopyridines, and reliance on stent implantation. The future, with new distal protection devices and drug-coated stents, should continue to see increased numbers of patients who can benefit from percutaneous intervention.     

Optimal pharmacological therapy in ST-elevation myocardial infarction—a review

Antithrombotic therapy is an essential component in the optimisation of clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. There are currently several intravenous anticoagulant drugs available for primary percutaneous coronary intervention. Dual antiplatelet therapy comprising aspirin and P2Y12 inhibitor represents the cornerstone treatment for STEMI. However, these effective treatment strategies may be associated with bleeding complications. Compared with clopidogrel, prasugrel and ticagrelor are more potent and predictable, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in primary percutaneous coronary intervention. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. In this review, we provide a critical and updated review of currently available antithrombotic therapies used in patients with STEMI undergoing primary PCI. Finding a balance that minimises both thrombotic and bleeding risk is difficult, but crucial. Further randomised trials for this optimal balance are needed.     

Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis

Objective To determine if there is a relation between aspirin “resistance” and clinical outcomes in patients with cardiovascular disease.Design Systematic review and meta-analysis.Data source Electronic literature search without language restrictions of four databases and hand search of bibliographies for other relevant articles.Review methods Inclusion criteria included a test for platelet responsiveness and clinical outcomes. Aspirin resistance was assessed, using a variety of platelet function assays.Results 20 studies totalling 2930 patients with cardiovascular disease were identified. Most studies used aspirin regimens, ranging from 75-325 mg daily, and six studies included adjunct antiplatelet therapy. Compliance was confirmed directly in 14 studies and by telephone or interviews in three. Information was insufficient to assess compliance in three studies. Overall, 810 patients (28%) were classified as aspirin resistant. A cardiovascular related event occurred in 41% of patients (odds ratio 3.85, 95% confidence interval 3.08 to 4.80), death in 5.7% (5.99, 2.28 to 15.72), and an acute coronary syndrome in 39.4% (4.06, 2.96 to 5.56). Aspirin resistant patients did not benefit from other antiplatelet treatment.Conclusion Patients who are resistant to aspirin are at a greater risk of clinically important cardiovascular morbidity long term than patients who are sensitive to aspirin.     

Gastric Bleeding and Benorylate,a New Aspirin

Benorylate (4-acetamidophenyl 2-acetoxybenzoate) is a new esterified aspirin preparation whose antirheumatic properties are reported to be as good as those of aspirin. Gastrointestinal blood loss, measured with ⁵¹Cr-labelled red cells, during benorylate therapy was compared with that during therapy with soluble aspirin in 15 subjects, a simplified crossover procedure being used. Mean blood loss during benorylate therapy was 1·7 ml/day which was significantly less than that during therapy with soluble aspirin (5·1 ml/day; P <0·001). In 12 of the 15 patients blood loss with benorylate was less than 2·5 ml/day. Benorylate appears to be a definite improvement on current formulations of aspirin and should be a useful drug for the treatment of patients with chronic rheumatic disorders.     

Eicosanoids in preeclampsia

Preeclampsia is characterized by an imbalance between two cyclooxygenase metabolites of arachidonic acid, thromboxane and prostacyclin, that favors thromboxane. Because of the biologic actions of these two eicosanoids, this imbalance might explain major clinical symptoms of preeclampsia, such as hypertension, platelet aggregation and reduced uteroplacental blood flow. In the maternal circulation, this imbalance is primarily manifested by decreased production of prostacyclin by endothelial cells. Platelet thromboxane synthesis is only increased in severe preeclampsia. In the placenta and in leukocytes, the imbalance is exacerbated by increased production of thromboxane coupled with decreased production of prostacyclin in both mild and severe preeclampsia. Longitudinal measurements of urinary metabolites of thromboxane and prostacyclin reveal that the thromboxane/prostacyclin imbalance predates the onset of clinical symptoms of preeclampsia. The imbalance between thromboxane and prostacyclin is most likely caused by oxidative stress, which is manifest in preeclampsia by increased lipid peroxidation and decreased antioxidant protection. Oxidative stress may drive this imbalance because lipid peroxides activate the cyclooxygenase enzyme to increase thromboxane synthesis, but at the same time they inhibit prostacyclin synthase to decrease prostacyclin synthesis. Low-dose aspirin therapy (50-150 mg/day) has been considered for the prevention of preeclampsia because it selectively inhibits thromboxane synthesis. Several studies reported dramatic decreases in the incidence of preeclampsia with low-dose aspirin therapy. However, two large multicenter studies reported only modest decreases, which dampened enthusiasm. The two large studies were "intent to treat" studies which included patients who were noncompliant and who discontinued the use of aspirin. In one of the studies for which compliance statistics were available only 53% of the aspirin group had a compliance rate greater than 75%, which raises a question as to whether the effectiveness of aspirin was being tested. Low-dose aspirin therapy should not yet be dismissed for the prevention of preeclampsia, but be reconsidered with emphasis on compliance using doses of aspirin in the range of 100-150 mg/day combined with antioxidants.     

氯吡格雷联合阿司匹林治疗老年冠心病的临床疗效观察

目的：探讨氯吡格雷联合阿司匹林治疗老年冠心病（CHD）的临床疗效和安全性。方法：60例老年CHD患者随机分为治疗组和对照组。对照组采用阿司匹林治疗,治疗组采用氯吡格雷联合阿司匹林治疗,治疗4周后观察血小板聚集率（PAG）和凝血功能。结果：治疗4周后,治疗组PAG显著下降,APTT显著上升,与治疗前和对照组比较均有显著性差异（P〈0.05）;两组治疗前后PT、PA变化差异无统计学意义（P〉0.05）。两组均未出现不良反应。结论：阿斯匹林联合氯吡格雷治疗老年CHD患者,较单用阿斯匹林治疗更能有效地抑制血小板聚集和预防血栓形成,并能得到更好的临床疗效。     

氯吡格雷联合阿司匹林治疗老年冠心病的临床疗效观察

目的:探讨氯吡格雷联合阿司匹林治疗老年冠心病(CHD)的临床疗效和安全性。方法:60例老年CHD患者随机分为治疗组和对照组。对照组采用阿司匹林治疗,治疗组采用氯吡格雷联合阿司匹林治疗,治疗4周后观察血小板聚集率(PAG)和凝血功能。结果:治疗4周后,治疗组PAG显著下降,APTT显著上升,与治疗前和对照组比较均有显著性差异(P<0.05);两组治疗前后PT、PA变化差异无统计学意义(P>0.05)。两组均未出现不良反应。结论:阿斯匹林联合氯吡格雷治疗老年CHD患者,较单用阿斯匹林治疗更能有效地抑制血小板聚集和预防血栓形成,并能得到更好的临床疗效。     

Remission-inducing drugs in rheumatoid arthritis.

The administration of certain drugs to patients with established rheumatoid arthritis frequently results in improvement that is slow to appear but persists for long periods, even after the drug is discontinued. The three main drugs with this effect, whose efficacy and toxicity are reviewed in this paper, are gold salts, D-penicillamine and chloroquine. The cytotoxic agents used to treat rheumatoid arthritis, which likely have nonspecific anti-inflammatory actions and have serious long-term side effects, are also briefly reviewed. A new drug, levamisole, is currently being tested in patients with rheumatoid arthritis. It is suggested that the time for considering the introduction of a remission-inducing drug in patients with progressive rheumatoid arthritis is after an adequate trial of therapy with salicylates or other nonsteroidal anti-inflammatory agents, or both, and before the oral administration of steroids. It is difficult, however, on the basis of rigorous clinical comparisons, to recommend which of the three main remission-inducing drugs should be tried first, although gold salts have been used the most. Patients who have improved with 6 months of chrysotherapy may continue treatment for at least 3 years, during which time the frequency of mucocutaneous and renal toxic effects will steadily decrease. Some aspects of the medical economics of therapy with remission-inducing drugs for rheumatoid arthritis are discussed.     

Controversies and future perspectives of antiplatelet therapy in secondary stroke prevention

Antiplatelet agents are a cornerstone in the treatment of acute arterial thrombotic events and in the prevention of thrombus formation. However, existing antiplatelet agents (mainly aspirin, the combination of aspirin and dipyridamole and clopidogrel) reduce the risk of vascular events only by about one quarter compared with placebo. As a consequence, more efficacious antiplatelet therapies with a reduced bleeding risk are needed. We give an overview of several new antiplatelet agents that are currently investigated in secondary stroke prevention: adenosine 5′-diphosphonate receptor antagonists, cilostazol, sarpogrelate, terutroban and SCH 530348. There are unique features in secondary stroke prevention that have to be taken into account: ischaemic stroke is a heterogeneous disease caused by multiple aetiologies and the blood–brain barrier is disturbed after stroke which may result in a higher intracerebral bleeding risk. Several small randomized trials indicated that the combination of aspirin and clopidogrel might be superior to antiplatelet monotherapy in the acute and early post-ischaemic phase. There is an ongoing debate about antiplatelet resistance. Decreasing response to aspirin is correlated independently with an increased risk of cardiovascular events. However, there is still no evidence from randomized trials linking aspirin resistance and recurrent ischaemic events. Similarly, randomized trials have not demonstrated a clinical significantly decreased antiplatelet effect by the concomitant use of clopidogrel and proton pump inhibitors. Nevertheless, a routine use of this drug combination is not recommended.     

Fault-il mettre en examen les antiplaquettaires et rechercher une résistance à l’aspirine?

Aspirin resistance leading to thrombotic recurrence has been extensively reported in the literature. However, its precise mechanisms and clinical outcomes are largely unknown. In this review, we report the conditions governing this resistance and the various tests proposed to explore it. The usefulness of monitoring aspirin therapy remains a debate.     

双联抗血小板治疗急性冠脉综合征临床疗效观察

目的：探讨双联抗血小板治疗急性冠脉综合征（ACS）的临床疗效和安全性。方法：60例ACS患者随机分为治疗组和对照组。对照组给予阿司匹林单抗血小板治疗,治疗组采用阿司匹林＋氯吡格雷双联抗血小板治疗,治疗3个月后评价临床疗效。结果：治疗组临床疗效总有效率为93.3%,显著高于对照组（76.7%）,相比较有显著性差异（P〈0.05）;治疗后,两组LVEF、CO、E/A显著上升,与治疗前比较均有显著性差异（P〈0.05）;且治疗组与对照组比较有显著性差异（P〈0.05）。结论：阿司匹林和氯吡格雷双联抗血小板药物治疗ACS,可以强化对血小板聚集的抑制,并增强抗栓效果,值得临床应用。     

双联抗血小板治疗急性冠脉综合征临床疗效观察

目的:探讨双联抗血小板治疗急性冠脉综合征(ACS)的临床疗效和安全性。方法:60例ACS患者随机分为治疗组和对照组。对照组给予阿司匹林单抗血小板治疗,治疗组采用阿司匹林+氯吡格雷双联抗血小板治疗,治疗3个月后评价临床疗效。结果:治疗组临床疗效总有效率为93.3%,显著高于对照组(76.7%),相比较有显著性差异(P<0.05);治疗后,两组LVEF、CO、E/A显著上升,与治疗前比较均有显著性差异(P<0.05);且治疗组与对照组比较有显著性差异(P<0.05)。结论:阿司匹林和氯吡格雷双联抗血小板药物治疗ACS,可以强化对血小板聚集的抑制,并增强抗栓效果,值得临床应用。     

Variability in the response to antiplatelet treatment in diabetes mellitus

Atherothrombosis is a leading cause of death in patients with diabetes mellitus. Among factors contributing to the diabetic prothrombotic state, platelet activation plays a pivotal role. Numerous studies have investigated the benefits of antiplatelet therapy for primary and secondary cardiovascular prevention in diabetic patients. However, there are limited evidences that low-dose aspirin may be effective in this clinical setting. Several disease-specific factors have been identified as potential determinants of aspirin treatment failure. In this review, the main determinants of interindividual variability in response to antiplatelet agents are discussed, with particular emphasis on the pharmacokinetic and pharmacodynamic mechanisms of clinical efficacy and safety of antiplatelet drugs in patients with diabetes mellitus.     

Plateletworks: a novel point of care platelet function screen

Platelet function is critically important in the acute-care settings of cardiopulmonary bypass surgery and percutaneous coronary intervention, which are commonly associated with the adverse vascular events of hemorrhage and thrombosis, respectively. To improve outcomes, it has been suggested that patients should be screened for platelet count and function periprocedurally, and therapeutic intervention including the possible use of thrombolytics and adequate anticoagulation or administration of antiplatelet agents, should be utilized. Antiplatelet therapy including aspirin (acetylsalicylic acid), the thienopyridines (clopidopgrel), and parenteral anti-glycoprotein (GP) IIb/IIIa agents (abciximab, tirofiban, and eptifibatide) are recognized as clinically important in patients at risk of developing thrombotic events. Recently, it has been recognized that empiric therapeutic administration of these agents may be suboptimal in clinical environments because of interpatient variability with regard to platelet count, platelet response, receptor concentration on the platelet, and other factors. Hence there is a clinical need to monitor such therapies on an individual basis. Traditional platelet tests including light transmission aggregometry (LTA) are inconvenient for acute diagnostic testing because of the complexity of the test and the requirement for specialty training. Hence, 'near-patient' test systems have recently been introduced. Plateletworks is an in vitro diagnostic, point-of-care test platform that has demonstrated utility in monitoring platelet response to all current antiplatelet agents including aspirin and clopidogrel.     

Observations on Drug Prescribing in Rheumatoid Arthritis

A total of 125 patients with rheumatoid arthritis were investigated about their drug therapy before referral to a specialist centre. Most referrals were from general practitioners. Only 47 of the patients had received salicylates as the first drug and 18 had never had them at all. Soluble aspirin was the preparation of salicylates most frequently prescribed (for 63 patients). Only 60 patients had been given an adequate dose and only 62 an adequate course of treatment with salicylates. In 28 patients salicylates had been stopped on account of side effects. About one-third of the patients had been prescribed oral corticosteroids.The referral letters were poor in giving details of past and present drug therapy, and there were serious omissions in reporting of previous side effects.Seventy-five general practitioners were asked to rate several currently marketed antirheumatic drugs in terms of effectiveness. Though prednisolone 15 mg daily ranked higher than aspirin 4 g daily the difference was not significant. The study shows the inadequacies of drug prescribing for rheumatoid arthritis in the Glasgow area.     

Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639

ABSTRACT: BACKGROUND: Coronary artery disease remains the dominant cause of mortality in developed countries. While platelets have been recognized to play a pivotal role in atherothrombosis, the ideal antiplatelet regime after coronary artery surgery remains elusive.The evolution of CABG has presently moved beyond technical improvements to involve modulation of pharmacologic management designed to improve patient outcomes. The aim of this trial will be to test the hypothesis that the addition of clopidogrel to patients with documented postoperative aspirin resistance will reduce the incidence of major cardiovascular events. METHODS: Patients scheduled for isolated coronary artery surgery will be eligible for the study. Patients in whom postoperative multiple electrode aggregometry documents aspirin resistance will be randomized into two groups. The control group will receive 300 mg of aspirin. The dual antiplatelet group will receive 75 mg of clopidogrel in addition to 300 mg of aspirin. Patients will be followed for 6 months. Major adverse cardiac and cerebrovascular events (death from any cause, myocardial infarction, stroke, hospitalization due to cardiovascular pathology) as well as bleeding events will be recorded. DISCUSSION: This will be the first trial that will specifically address the issue of dual antiplatelet therapy in patients undergoing coronary artery surgery who have been found to be aspirin resistant. In the event that the addition of clopidogrel proves to be beneficial in this subset of surgical patients, this study could significantly impact their future antiplatelet management.This randomized controlled trial has been registered at the ClinicalTrials.gov website (Identifier NCT01159639).     

Effects of vitamin C and aspirin in ischemic stroke-related lipid peroxidation: results of the AVASAS (Aspirin Versus Ascorbic acid plus Aspirin in Stroke) Study

A condition of oxidative stress is known to occur in ischemic stroke, the current therapeutic intervention of which is largely limited to thrombolysis. To assess the effect of vitamin C - in conjunction to aspirin - in ischemic stroke-related lipid peroxidation, we measured plasma levels of ascorbate, of 8,12-isoprostanes F2alpha-VI (8,12-iPF2alpha-VI) and activities and levels of a broad spectrum of antioxidant enzymes and micronutrients in stroke patients randomized to receive, from stroke onset and up to three months, either vitamin C (200 mg/day) plus aspirin (300 mg/day) or only aspirin (300 mg/day). By the end of the first week, patients treated with vitamin C plus aspirin had higher vitamin C levels (p = 0.02) and lower 8,12-iPF2alpha-VI levels (p = 0.01) than patients treated with aspirin alone. The significance was maintained for the increase of vitamin C after three months of therapy (p < 0.01). The clinical functional outcome for both groups of patients similarly ameliorated after three months of treatment. We conclude that vitamin C, at the dose of 200 mg/day and in conjunction with aspirin, significantly decreases ischemic stroke-related lipid peroxidation in humans. Further studies are warranted to clarify whether the use of vitamin C may add clinical long-term beneficial effects in patients with stroke.