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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 19 recordsLinked to original sources
PubMed2004

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Adult↗
PubMed2001

Prevention and treatment of postphlebitic syndrome: results of a 3-part study.

BACKGROUND: The true incidence of postphlebitic syndrome (PPS) following proximal deep venous thrombosis (DVT) and the efficacy of graduated compression stockings in preventing and treating PPS are unknown. METHODS: A 3-part study of 202 patients evaluated 1 year after proximal DVT: 2 randomized placebo-controlled trials of stockings and 1 prospective cohort of untreated patients. Patients were evaluated for PPS, using a standardized questionnaire, and for venous valvular incompetence, using photoplethysmography and venous Doppler. They were enrolled in study 1 or study 2 if they did not have symptomatic PPS and did not have or had venous valvular incompetence, respectively, and into study 3 if they had symptomatic PPS. Study 1 patients were left untreated and followed up for development of PPS every 6 months for a mean of 55 months. Study 2 patients were randomized to a below-knee stocking (20-30 mm Hg) or a matched placebo stocking, and followed up for development of PPS every 6 months for a mean of 57 months. Study 3 patients were randomized to an active stocking (30-40 mm Hg) or a matched placebo stocking and followed up every 3 months for treatment failure, defined a priori. RESULTS: In study 1, 6 (5.0%) of 120 patients were categorized as treatment failures, a rate similar to placebo-treated study 2 patients (P =.10). In study 2, 0 (0%) of 24 active and 1 (4.3%) of 23 placebo-treated patients were categorized as treatment failures (P =.49). In study 3, 11 (61.1%) of 18 active and 10 (58.8%) of 17 placebo-treated patients were categorized as treatment failures (P>.99). CONCLUSIONS: Most patients do not have PPS 1 year after proximal DVT, and do not require stockings. We failed to show a benefit of stockings in patients with PPS, but the small numbers preclude definitive conclusions.

Adolescent↗
PubMed2001

Management of suspected deep venous thrombosis in outpatients by using clinical assessment and D-dimer testing.

BACKGROUND: When deep venous thrombosis is suspected, objective testing is required to confirm or refute the diagnosis. OBJECTIVE: To determine whether the combination of a low clinical suspicion and a normal D -dimer result rules out deep venous thrombosis. DESIGN: Prospective cohort study. SETTING: Three tertiary care hospitals in Canada. PATIENTS: 445 outpatients with a suspected first episode of deep venous thrombosis. INTERVENTIONS: Patients were categorized as having low, moderate, or high pretest probability of thrombosis and underwent whole-blood D -dimer testing. Patients with a low pretest probability and a negative result on the D -dimer test had no further diagnostic testing and received no anticoagulant therapy. Additional diagnostic testing was done in all other patients. MEASUREMENTS: Venous thromboembolic events during 3-month follow-up. RESULTS: 177 (40%) patients had both a low pretest probability and a negative D -dimer result. One of these patients had deep venous thrombosis during follow-up (negative predictive value, 99.4% [95% CI, 96.9% to 100%]). CONCLUSION: The combination of a low pretest probability of deep venous thrombosis and a negative result on a whole-blood D -dimer test rules out deep venous thrombosis in a large proportion of symptomatic outpatients.

Ambulatory Care↗
PubMed2001

Reactivation of ischemic events in acute coronary syndromes: results from GUSTO-IIb. Gobal Use of Strategies To Open occluded arteries in acute coronary syndromes.

OBJECTIVES: We sought to determine the incidence of and risk factors for thrombotic events early after discontinuing antithrombin therapy in patients with acute coronary syndromes. BACKGROUND: Discontinuation of treatment with heparin and other thrombin inhibitors in patients with unstable coronary syndromes has related to clinical and biochemical evidence of early reactivation of thrombosis. METHODS: We studied 8,943 of the 12,142 patients with acute coronary syndromes enrolled in the Global Use of Strategies To Open occluded arteries in acute coronary syndromes trial of hirudin versus heparin. We excluded patients who received no study drug, lacked timing data, died or had myocardial (re)infarction [(re)MI] during study-drug infusion, or began heparin treatment within 2 h after treatment with the study drug was stopped. We assessed the incidence and timing of (re)MI by type and timing of antithrombin treatment. RESULTS: In all, 215 patients (2.4%) suffered (re)MI, 49 within 12 h of antithrombin therapy discontinuation and 166 between hour 12 and hospital discharge. The duration of infusion did not differ between the hirudin and heparin groups. The rate of early re(MI) after drug therapy discontinuation was significantly higher in patients given heparin versus hirudin (0.8% vs. 0.3%, p = 0.002). Patients with (re)MI had higher mortality at 30 days (23.6% vs. 2.4%, p = 0.001) and 1 year (35.2% vs. 6.7%, p = 0.001) compared with patients without (re)MI. CONCLUSIONS: The incidence of (re)MI was clustered within 12 h of heparin therapy discontinuation, with the greatest risk within 4 h. There was no evidence of early reactivation of thrombotic events after hirudin. Patients who had (re)infarction had worse outcomes. Better understanding of the mechanism and possible prevention of recurrent thrombosis is needed.

Aged↗
PubMed2001

Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective.

In 1960, Barritt and Jordan performed the first randomized trial demonstrating the efficacy of anticoagulant therapy in the treatment of venous thromboembolism. Since then, important therapeutic advances have been made in the treatment of deep venous thrombosis and pulmonary embolism. This paper reviews the important clinical trials involving anticoagulant therapy and vena caval interruption. The studies are discussed from a historical perspective, and an attempt is made to analyze both the thought processes that prompted their design and the reasons why they changed practice.

Anticoagulants↗
PubMed2001

Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin.

BACKGROUND: The commonly recommended therapeutic range for patients receiving unfractionated heparin of 1.5 to 2.5 times the control activated partial thromboplastin time (aPTT) is not universally applicable. It has been suggested that the therapeutic range for each aPTT reagent should be based on plasma heparin levels. We sought to identify an aPTT ratio that corresponds to therapeutic anti--factor Xa heparin levels for combinations of several reagents and coagulometers that are commonly used. METHODS: Citrated plasma was collected from 126 unselected patients receiving unfractionated heparin. Four automated coagulometers and 6 commercial aPTT reagents were used to measure the aPTT. Plasma anti--factor Xa levels were measured by means of a commercially available assay. The relationship between the aPTT results and anti-factor Xa heparin levels for each reagent-coagulometer combination was determined by linear regression analysis, and the aPTT results corresponding to therapeutic anti--factor Xa heparin levels were calculated. RESULTS: For all reagent-coagulometer combinations studied, an aPTT ratio of 1.5 resulted in anti--factor Xa heparin levels considerably below the lower limit of the therapeutic range. When the aPTT was performed on any of the coagulometers assessed with the use of Actin (Dade Diagnostics, Aguada, Puerto Rico) and IL Test (Instrumentation Laboratories, Fisher Scientific, Unionville, Ontario) reagents, aPTT ratios necessary to achieve therapeutic anti--factor Xa heparin levels approximated 2.0 to 3.5. CONCLUSION: For laboratories that cannot perform heparin levels, the use of less responsive reagents and any of the coagulometers studied, along with target aPTT ratio between 2.0 and 3.5, appears to be a reasonable alternative.

Antithrombin III↗
PubMed2001

Developing a novel antithrombotic in the academic environment.

In recent years, academic research institutions have increasingly sought to commercialize their discoveries, providing the opportunity to raise venture capital and benefit financially from their developments. In the last 6 years, Hamilton Civic Hospitals Research Center, affiliated with McMaster University, Ontario, Canada, has set up two companies, Vascular Therapeutics and Osteokine, to commercialize its discoveries in thrombosis and osteoporosis. Epidemiological evidence shows a continuing socioeconomic burden of both of these disorders, thereby offering opportunities for new drug development. Key areas in the field of thrombosis include novel parenteral anticoagulants to replace heparin as adjunctive therapy in acute coronary syndromes, safer and more practical oral anticoagulants that do not require monitoring to replace coumarins, and oral antiplatelet drugs for use in combination with aspirin. Since their creation, Vascular Therapeutics and Osteokine have attracted major funding and developed several patentable compounds that show clinical and commercial promise.

Academies and Institutes↗
PubMed2001

Randomized comparison of a novel anticoagulant, vasoflux, and heparin as adjunctive therapy to streptokinase for acute myocardial infarction: results of the VITAL study (Vasoflux International Trial for Acute Myocardial Infarction Lysis).

BACKGROUND: Vasoflux is a low-molecular-weight heparin derivative that inhibits factor IXa activation of factor X and catalyzes fibrin-bound thrombin inactivation by heparin cofactor II. We studied whether vasoflux improves the results of thrombolysis with streptokinase for acute myocardial infarction. METHODS AND RESULTS: We randomized 277 patients with acute myocardial infarction to standard intravenous unfractionated heparin (UFH) or intravenous vasoflux 1, 4, 8, or 16 mg/kg as a bolus followed by 1, 4, 8, or 16 mg/kg per hour infusion, on top of streptokinase and aspirin, until angiography at 90 minutes. Patency and corrected Thrombolysis in Myocardial Infarction (TIMI) frame count were studied at 60 and 90 minutes. Rates of TIMI grade 3 flow with vasoflux at any dose (35% to 42%) were not different from UFH (41%) at either time point, nor was the corrected TIMI frame count. However, there was an excess of bleeding in the patients randomized to vasoflux 8 or 16 mg/kg: 78% and 71%, compared with 53% for UFH (P =.004 and.043, respectively). Major bleeding was observed in 13% and 28% at these vasoflux doses compared with 8% with UFH (P =.558 and.01, respectively). CONCLUSION: At doses that increase the risk of bleeding, the addition of vasoflux to streptokinase and aspirin did not lead to improved patency rates compared with UFH. Targeting factor IXa and heparin cofactor II may not be a useful adjunct to thrombolysis.

Adult↗
PubMed2001

New anticoagulants.

BACKGROUND: Heparin and coumarins have been in clinical use for more than 50 years. Low-molecular-weight heparins (including a heparinoid), developed 25 years ago, have been used clinically for more than a decade. METHODS: In the last 10 years, several new anticoagulants that target almost every step in the coagulation pathway have been developed. Of these, 3 direct thrombin inhibitors (hirudin, bivalirudin, and argatroban) are approved for clinical use. Four other anticoagulants (activated protein C, tissue factor pathway inhibitor, synthetic pentasaccharide, and the oral thrombin inhibitor H376/95) are being evaluated or have completed evaluation in phase III studies; various other compounds are in phase II studies. RESULTS: The mechanism of action, sites of action, and potential clinical indications of these new anticoagulants are reviewed. CONCLUSIONS: To compete effectively, the new oral anticoagulants currently under development will have to be at least as effective and safe as coumarins, oral thrombin, or Factor Xa inhibitors and require less monitoring.

Anticoagulants↗
PubMed2001

The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines.

Extracellular concentrations of monoamine neurotransmitters are regulated by a family of high-affinity transporters that are the molecular targets for such psychoactive drugs as cocaine, amphetamines, and therapeutic antidepressants. In Drosophila melanogaster, cocaine-induced behaviors show striking similarities to those induced in vertebrate animal models. Although a cocaine-sensitive serotonin carrier exists in flies, there has been no pharmacological or molecular evidence to support the presence of distinct carrier subtypes for other bioactive monoamines. Here we report the cloning and characterization of a cocaine-sensitive fly dopamine transporter (dDAT). In situ hybridization demonstrates that dDAT mRNA expression is restricted to dopaminergic cells in the fly nervous system. The substrate selectivity of dDAT parallels that of the mammalian DATs in that dopamine and tyramine are the preferred substrates, whereas octopamine is transported less efficiently, and serotonin not at all. In contrast, dDAT inhibitors display a rank order of potency most closely resembling that of mammalian norepinephrine transporters. Cocaine has a moderately high affinity to the cloned dDAT (IC50 = 2.6 microM). Voltage-clamp analysis of dDAT expressed in Xenopus laevis oocytes indicates that dDAT-mediated uptake is electrogenic; however, dDAT seems to lack the constitutive leak conductance that is characteristic of the mammalian catecholamine transporters. The combination of a DAT-like substrate selectivity and norepinephrine transporter-like inhibitor pharmacology within a single carrier, and results from phylogenetic analyses, suggest that dDAT represents an ancestral catecholamine transporter gene. The identification of a cocaine-sensitive target linked to dopaminergic neurotransmission in D. melanogaster will serve as a basis for further dissection of the genetic components of psychostimulant-mediated behavior.

Amino Acid Sequence↗