Subject(s)
Anticoagulants , Administration, Oral , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Atrial Fibrillation/prevention & control , Coumarins/pharmacology , Coumarins/therapeutic use , Drug Interactions , Food , Heart Valve Prosthesis , Humans , Myocardial Infarction/drug therapy , Thromboembolism/prevention & control , Venous Thrombosis/prevention & control , Warfarin/pharmacology , Warfarin/therapeutic useSubject(s)
Anticoagulants/therapeutic use , Administration, Oral , Age Factors , Aged , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/pharmacokinetics , Antiphospholipid Syndrome , Blood Coagulation Tests , Female , Hemorrhage/chemically induced , Humans , International Normalized Ratio , Models, Theoretical , Pregnancy , Risk FactorsSubject(s)
Anticoagulants/administration & dosage , Warfarin/administration & dosage , Administration, Oral , Anticoagulants/adverse effects , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Drug Interactions , Drug Monitoring , Humans , Prothrombin Time , Vitamin K 1/therapeutic use , Warfarin/adverse effects , Warfarin/pharmacology , Warfarin/therapeutic useABSTRACT
The Department of Veterans Affairs, through its Cooperative Studies Program, has a long history of conducting large-scale, multihospital biomedical clinical trials. The agency's Health Services Research and Development Service, although newer, has a distinguished record of mainly single-site research into the organization, delivery, and financing of health services. In 1990, a joint program was initiated to conduct multicenter studies in health services research. This article describes the studies developed in the new program and the research design issues encountered in planning them. Identification of the patient population, specification and measurement of the intervention, and description of the control group, as well as attention to the unit of randomization and analysis, outcome variables and choice of effect size, data quality, and ethical considerations are among the important issues related to the design of these studies and future studies in health services.
Subject(s)
Delivery of Health Care/organization & administration , Health Services Research/organization & administration , Multicenter Studies as Topic/methods , Randomized Controlled Trials as Topic/methods , United States Department of Veterans Affairs , Forecasting , Humans , Research Design , United StatesABSTRACT
Rapid reduction of excessively high international normalized ratio (INR) values into the therapeutic range is necessary in patients who must be maintained on oral anticoagulants but who present with an overdose. We prospectively studied the effect of observation alone versus escalating low doses of intravenous vitamin K on 23 patients presenting with no overt evidence of hemorrhage and INR values in excess of 10. Two of six patients observed without intervention developed spontaneous hemorrhage. Only one of the observed patients and none of 4 patients given 100-200 µg-vitamin K had INR values less than 5.0 by 24 hours. Three of the four patients receiving 500 µg of vitamin K had INR values less than 5.0, with two of these being less than 3.5 within the first 24 hours. Nine patients receiving 1000 µg of vitamin K had INR values between 1.7 and 3.5 by 24 hours. In none of these nine patients did the INR subsequently normalize, and there were no difficulties re-establishing anticoagulant therapy. No adverse effects were noted in any of the patients receiving intravenous vitamin K. We recommend 1000 µg of intravenous vitamin K as a safe and effective means of rapidly reversing excessively anticoagulated patients presenting with INR values greater than 10 units.
Subject(s)
Anticoagulants/administration & dosage , Administration, Oral , Anticoagulants/adverse effects , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Clinical Trials as Topic , Humans , Time Factors , Warfarin/administration & dosage , Warfarin/adverse effects , Warfarin/pharmacokinetics , Warfarin/pharmacologySubject(s)
Anticoagulants/pharmacology , Heparin/pharmacology , Animals , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/pharmacokinetics , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Monitoring , Heparin/administration & dosage , Heparin/adverse effects , Heparin/pharmacokinetics , Humans , Safety , Thrombocytopenia/chemically inducedABSTRACT
We performed a metaanalysis of five randomized controlled trials to compare the efficacy and safety of combined oral anticoagulant and antiplatelet therapy versus oral anticoagulants alone after prosthetic heart-valve replacement. The combined regimen reduced embolism and overall mortality by approximately 67% (pooled odds ratio [OR] 0.33; 95% confidence interval [CI] 0.16 to 0.69; p = 0.0032) and 40% (OR 0.60; 95% CI 0.32 to 1.12; p = 0.11), respectively, but increased the risk of hemorrhage by approximately 65% (OR 1.65; 95% CI 1.15 to 2.39; p = 0.0069) and of major gastrointestinal hemorrhage by approximately 250% (OR 3.47; 95% CI 1.43 to 8.40; p = 0.0058). It is estimated that for every 1.6 patients who had their stroke prevented by combination therapy, there was an excess of one major gastrointestinal bleed. This metaanalysis suggests that the benefits derived from the enhanced antithrombotic potential of combined therapy outweigh the toxic effects resulting from the enhanced anticoagulant potential of this regimen.
Subject(s)
Anticoagulants/therapeutic use , Heart Valve Prosthesis , Platelet Aggregation Inhibitors/therapeutic use , Postoperative Care , Administration, Oral , Anticoagulants/adverse effects , Confidence Intervals , Drug Therapy, Combination , Humans , Odds Ratio , Platelet Aggregation Inhibitors/adverse effects , Randomized Controlled Trials as Topic , Risk Assessment , Safety , Sensitivity and Specificity , Treatment OutcomeABSTRACT
The term hemostasis refers to the critical physiologic response to arterial injury that serves to limit hemorrhage. Thrombosis, a pathologic process, results when the coagulation system is excessively activated in the absence of bleeding. The mechanisms that regulate these processes, as well as the mode of action of pharmacologic agents that attenuate thrombosis, are discussed.
Subject(s)
Hemostasis , Thrombosis , Angina, Unstable/blood , Angina, Unstable/etiology , Blood Coagulation Factors , Fibrinolysis , Fibrinolytic Agents , Humans , Myocardial Infarction/blood , Myocardial Infarction/etiology , Platelet Activation , Thrombosis/bloodABSTRACT
This article addresses the efficacy and safety of antiplatelet and anticoagulant agents following acute myocardial infarction. Major trials are reviewed for both of these treatment modalities in the order in which they were published. Accompanying editorial comments highlight the key findings of the studies and places them in historical context. Current recommendations for treatment are summarized. Antithrombotic therapy used as an adjuvant to thrombolytic therapy is discussed elsewhere.
Subject(s)
Anticoagulants/therapeutic use , Myocardial Infarction/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Anticoagulants/administration & dosage , Clinical Trials as Topic , Humans , Platelet Aggregation Inhibitors/administration & dosage , Research DesignABSTRACT
The greater precision in prothrombin time monitoring obtained using thromboplastins with low international sensitivity index (ISI) values are believed to result in improved patient care. The authors conducted a blinded prospective study of 84 random patients on low-intensity warfarin therapy who were monitored with either a sensitive (ISI, 1.3) or standard (ISI, 1.9) thromboplastin. For the patients monitored with standard and sensitive thromboplastins, respectively, no difference was found in the degree of anticoagulation (standard thromboplastin mean INR, 2.4 vs. 2.5, P = .37; sensitive thromboplastin mean INR, 2.6 vs. 2.6, P = .74; mean daily warfarin dose, 5.1 vs. 4.7 mg, P = .28) or efficacy (warfarin dosage adjustments, 117 vs. 116; clinic visits, 362 vs. 378; percentage of therapeutic INR determinations, 47% vs. 48%). In addition, no difference was found in bleeding prevalence or severity (.22 vs. .27 events per person-year observation). The authors concluded that monitoring anticoagulant therapy in the INR range of 2-3 with a standard thromboplastin may be comparable to monitoring with a more sensitive thromboplastin with respect to efficacy, safety, and degree of anticoagulation achieved.
Subject(s)
Prothrombin Time , Thromboplastin/chemistry , Warfarin/administration & dosage , Administration, Oral , Aged , Double-Blind Method , Drug Monitoring/methods , Female , Humans , Male , Prospective Studies , Reference Standards , Warfarin/adverse effectsABSTRACT
Human platelets secreted phospholipase A2 in a dose- and time-dependent manner when challenged with thrombin, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), or collagen. Enzyme release was maximal at concentrations of 0.1 units/ml of thrombin, 100 nM TPA, or 2 micrograms/ml of collagen; and complete by 2 min in platelets treated with thrombin or TPA. Cells challenged with collagen required up to 5 min for maximal secretion. Besides dose and time functions, phospholipase A2 secretion was also dependent on platelet concentration and the levels of bovine serum albumin in the incubation medium. The secreted enzyme was soluble and exhibited substrate and Ca2+ requirements similar to a detergent-solubilized, partially purified phospholipase A2 from whole platelets [Kramer et al., Biochim. Biophys. Acta (1988) 959, 269-279]. The pH optimum of the secreted enzyme, however, was 1-2 units lower than the pH optimum of the phospholipase A2 from whole cells. Secreted phospholipase A2 hydrolyzed phosphatidylethanolamine at 5-12 times the rate of phosphatidylcholine when the substrates were present in pure form. These apparent differences in activity were greatly diminished, though, when 1:1 molar mixtures of the two substrates were employed. Because phospholipase A2 catalyzes a key reaction during the formation of bioactive arachidonate metabolites, the secretion of this enzyme from platelets may be important in the regulation of thrombosis.
Subject(s)
Blood Platelets/metabolism , Phospholipases A/metabolism , Blood Platelets/drug effects , Blood Platelets/enzymology , Calcium/pharmacology , Collagen/pharmacology , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Phospholipases A/blood , Phospholipases A2 , Serum Albumin, Bovine/pharmacology , Tetradecanoylphorbol Acetate/pharmacology , Thrombin/pharmacologyABSTRACT
The ability of the prothrombin time to measure the anticoagulant effect of warfarin sodium varies depending on the particular tissue thromboplastin used in performing the test. Based on studies using sensitive thromboplastins, lower therapeutic ranges of anticoagulation are recommended. The adequacy of monitoring therapy in this lower range with the relatively insensitive thromboplastins commonly used in North America is unestablished. This 16-month prospective study used a standard North American thromboplastin to monitor 157 anticoagulated patients treated in a low therapeutic range. Of the 1734 prothrombin times generated, 876 (56%) were therapeutic, with 400 (23%) below and 458 (26%) above the therapeutic range. These results are comparable with those published in trials in which more sensitive thromboplastins were used in a similar therapeutic range. We conclude that standard North American thromboplastins are adequately suited to monitor therapy in this lower range.
Subject(s)
Anticoagulants/administration & dosage , Monitoring, Physiologic , Thromboplastin , Aged , Anticoagulants/therapeutic use , Female , Humans , International Cooperation , Male , Middle Aged , Prospective Studies , Prothrombin Time , Reference Standards , Regression Analysis , Sensitivity and Specificity , Thromboplastin/chemistryABSTRACT
Ethical dilemmas caused by external events and an interim subset analysis raised concerns about continuing a long-term VA clinical trial comparing early with later zidovudine therapy for symptomatic human immunodeficiency virus (HIV) infection. The first external event was the early termination of other, apparently similar, trials conducted by the AIDS Clinical Trials Group (ACTG) and the announced clear benefits for the zidovudine-treated patients. Interim analysis of the VA trial at this time did not show similar benefits. Subset analyses were performed to explore factors that might explain the different results. These suggested a difference in response to zidovudine in white and minority groups. The Data Monitoring Board and a special advisory panel reviewed these data and concluded that, since the VA results were neutral overall and the subset analyses based on small numbers, the trial should continue. By conference call, the study cochairmen and biostatistician discussed this decision with study personnel without revealing interim results, and study personnel passed the information on to patients at the participating centers. The second event was in March 1990, when the Food and Drug Administration (FDA) approved earlier use of zidovudine, which applied to patients still in the VA trial. Patients were asked to reaffirm their participation by signing a new informed consent that explained the findings reported by the ACTG, the FDA-approved revised recommendations, and the rationale for continuation of the VA trial. The consent form emphasized that continued masked therapy was optional and that unmasked treatment and follow-up would be provided to patients requesting it. Seventy-four percent of the participants chose to continue masked therapy. We conclude that when new external data are announced, informed participation in a long-term clinical trial may require a revised consent form and that it is ethical and practical to present this without disclosure of interim study results.
Subject(s)
Clinical Trials as Topic , Ethics, Medical , HIV Infections/drug therapy , Risk Assessment , Therapeutic Human Experimentation , Zidovudine/administration & dosage , Acquired Immunodeficiency Syndrome/drug therapy , Acquired Immunodeficiency Syndrome/immunology , Acquired Immunodeficiency Syndrome/mortality , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Clinical Trials as Topic/legislation & jurisprudence , Consent Forms , Double-Blind Method , Drug Administration Schedule , Federal Government , HIV Infections/immunology , HIV Infections/mortality , Humans , Informed Consent/legislation & jurisprudence , Leukocyte Count/drug effects , Zidovudine/adverse effectsABSTRACT
Membranes isolated from porcine aortic endothelial cells (PAEC) contain a CoA-independent transacylase enzyme (CoA-IT). CoA-IT, an integral membrane protein, transfers an acyl moiety to added [3H]alkylhydroxyglycerophosphocholine (LPAF) to generate [3H]alkylacylglycerophosphocholine (alkylacyl-GPC). This enzyme exhibits an apparent Km of 0.7 microM and a Vmax of 0.8 nmol/min per mg for the transfer of an acyl group to added [3H]LPAF. The addition of the nonionic detergent Triton X-100 (TX-100) (0.5 mg/ml), the sulfhydryl reagents N-ethylmaleimide (NEM) (200 microM) or thimerosal (200 microM), or pre-incubating the membranes at 95 degrees C for 10 min all decreased LPAF: CoA-IT activity by more than 95%. The inhibitory action of NEM or thimerosal suggests that sulfhydryl group(s) are involved in or are close to the catalytic site of LPAF: CoA-IT.
Subject(s)
Acyltransferases/metabolism , Coenzyme A/metabolism , Endothelium, Vascular/enzymology , Phosphatidylcholines/metabolism , Acyltransferases/antagonists & inhibitors , Animals , Cell Membrane/enzymology , Kinetics , SwineABSTRACT
Cultured porcine aortic endothelial cells were conditioned in normal (5.2 mM) and elevated (15.6 mM) glucose, prelabeled with [14C]arachidonic acid and stimulated with ionophore A23187. Elevated glucose cultures released less radiolabeled products and less [14C]arachidonic acid. Analysis of cellular lipids revealed that elevated glucose reduced net loss of radiolabel from diacylphosphatidylethanolamine, did not affect early phosphatidylinositol hydrolysis, and increased net loss from diacylphosphatidylcholine and alkenylacylphosphatidylethanolamine. Uptake of radiolabel upon stimulation was examined to measure the role of reacylation on the diminished net release of radiolabel in elevated glucose cultures. Enhanced acylation of [3H]arachidonic acid into cellular lipids, especially PI, was observed in stimulated and resting cultures with elevated glucose. Further, pretreatment of the cultures with an acyltransferase inhibitor, thimerosal, prior to A23187 stimulation in radiolabeled cultures, abolished the effects of glucose on eicosanoid and arachidonic acid release. Differences in the ionophore-induced net loss of radiolabel from diacylphosphatidylethanolamine and phosphatidylinositol of the two glucose treatments were diminished by thimerosal exposure, while net loss of radiolabel from diacylphosphatidylcholine and alkenylacylphosphatidylethanolamine were unaffected. The data indicate that elevated glucose alters deacylation and enhances reacylation of arachidonic acid into endothelial cells and particularly into phosphatidylinositol. Enhanced reacylation may explain some of the altered lipid pathways that have been observed in experiments that elevate glucose concentrations or involve diabetes.
Subject(s)
Arachidonic Acid/metabolism , Calcimycin/pharmacology , Endothelium, Vascular/drug effects , Glucose/pharmacology , Acylation , Animals , Aorta , Cells, Cultured , Endothelium, Vascular/metabolism , Swine , Thimerosal/pharmacologySubject(s)
Blood Coagulation/drug effects , Heparin, Low-Molecular-Weight/pharmacology , Heparin/pharmacology , Dose-Response Relationship, Drug , Drug Monitoring , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Osteoporosis/chemically induced , Thrombocytopenia/chemically induced , Thrombophlebitis/drug therapySubject(s)
Anticoagulants , Cardiovascular Diseases/drug therapy , Warfarin , Administration, Oral , Anticoagulants/administration & dosage , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Cardiovascular Diseases/prevention & control , Female , Heart Valve Prosthesis , Humans , Pregnancy , Vitamin K/therapeutic use , Warfarin/antagonists & inhibitors , Warfarin/pharmacology , Warfarin/therapeutic useABSTRACT
OBJECTIVE: To determine whether carotid endarterectomy provides protection against subsequent cerebral ischemia in men with ischemic symptoms in the distribution of significant (greater than 50%) ipsilateral internal carotid artery stenosis. DESIGN: Prospective, randomized, multicenter trial. SETTING: Sixteen university-affiliated Veterans Affairs medical centers. PATIENTS: Men who presented within 120 days of onset of symptoms that were consistent with transient ischemic attacks, transient monocular blindness, or recent small completed strokes between July 1988 and February 1991. Among 5000 patients screened, 189 individuals were randomized with angiographic internal carotid artery stenosis greater than 50% ipsilateral to the presenting symptoms. Forty-eight eligible patients who refused entry were followed up outside of the trial. OUTCOME MEASURES: Cerebral infarction or crescendo transient ischemic attacks in the vascular distribution of the original symptoms or death within 30 days of randomization. INTERVENTION: Carotid endarterectomy plus the best medical care (n = 91) vs the best medical care alone (n = 98). RESULTS: At a mean follow-up of 11.9 months, there was a significant reduction in stroke or crescendo transient ischemic attacks in patients who received carotid endarterectomy (7.7%) compared with nonsurgical patients (19.4%), or an absolute risk reduction of 11.7% (P = .011). The benefit of surgery was more profound in patients with internal carotid artery stenosis greater than 70% (absolute risk reduction, 17.7%; P = .004). The benefit of surgery was apparent within 2 months after randomization, and only one stroke was noted in the surgical group beyond the 30-day perioperative period. CONCLUSIONS: For a selected cohort of men with symptoms of cerebral or retinal ischemia in the distribution of a high-grade internal carotid artery stenosis, carotid endarterectomy can effectively reduce the risk of subsequent ipsilateral cerebral ischemia. The risk of cerebral ischemia in this subgroup of patients is considerably higher than previously estimated.