Search PubMed⌕ Search

Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 127 records · Page 7Linked to original sources
PubMed1996

Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis.

PURPOSE: To obtain reliable estimates of the relative efficacy and safety of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) in the treatment of patients with venous thromboembolism. METHODS: A literature search of randomized trials evaluating LMWH and UFH for the period from 1980 to 1994 was conducted to obtain data for a meta-analysis. Studies were classified as level 1 if they were double-blind or if there was blinded assessment of outcome measures, and level 2 if they did not provide assurance of blinded outcome assessment. RESULTS: In level 1 studies, the relative risk (RR) of recurrent venous thromboembolism during the first 15 days and over the entire period of anticoagulant therapy was 0.24 (95% confidence intervals [CI] 0.06 to 0.80, P = 0.02) and 0.39 (95% CI 0.30 to 0.80, P = 0.006), respectively, in favor of LMWH treatment. The RR for major bleeding was 0.42 (95% CI 0.2 to 0.9, P = 0.01), in favor of LMWH. In level 2 studies, no significant differences in the rates of recurrent venous thromboembolism or major bleeding were observed. Pooling level 1 and level 2 studies, the RR for overall mortality and mortality in cancer patients was 0.51 (95% CI 0.2 to 0.9, P = 0.01), and 0.33 (95% CI 0.1 to 0.8, P = 0.01), respectively in favor of LMWH. CONCLUSIONS: LMWH are likely to be more effective than UFH in preventing recurrent venous thromboembolism, to produce less major bleeding, and to be associated with a lower mortality rate, particularly in the subgroup of patients with cancer.

Acute Disease↗
PubMed1996

Reliability of the international normalized ratio for monitoring the induction phase of warfarin: comparison with the prothrombin time ratio.

The International Normalized Ratio (INR) was introduced to reduce the variability of prothrombin time (PT) reporting. One potential problem with the use of the INR is the assumption that its reliability is reduced when it is used to monitor patients during the induction phase of treatment. This shortcoming arises because the model used to establish the INR system is based on the use of pooled plasma from patients stabilized on warfarin for at least 6 weeks. Because the prolongation of the PT by warfarin during the induction phase mainly reflects reduction in factor VII levels (whereas the prolongation of the PT after 6 weeks of stabilization reflects reductions in factors X, II, and VII), there exists a potential for loss of accuracy of the INR during warfarin induction. To overcome this potential problem, it has been suggested that the PT ratio should be used to report results during the induction phase of treatment and that the INR system should be reserved for reporting results after the patient has been stabilized. This approach is confusing to the clinician. In addition, the validity of this approach has never been demonstrated in a clinical study. To address this issue, we studied 43 patients for the first 5 days after they started warfarin therapy. We measured the PT in the same plasma samples from each patient with five different commercial thromboplastins. The variance in the PT ratios among the five thromboplastins was compared with the variance obtained with the INR values derived from the PT ratios when using the international sensitivity indexes provided by the manufacturer. Our results indicate that, even during the induction phase, there is less variance with the INR system than with the PT ratio system.

Anticoagulants↗
PubMed1996

Multicentric evaluation of heparinase on aPTT, thrombin clotting time and a new PT reagent based on recombinant human tissue factor.

In a multicentric study the influence of heparinase (Hepzyme) was evaluated on activated partial thromboplastin time, thrombin clotting time and prothrombin time using the recombinant human tissue factor and synthetic phospholipid (phosphatidylcholine and phosphatidyl-serine reagent). Hepzyme itself does not have any influence on normal coagulation values of activated partial thromboplastin time (aPTT) and prothrombin time (PT) assays whereas thrombin clotting time was prolonged by 10% (n = 60). In patients treated with unfractionated heparin for recent deep vein thrombosis (n = 47), plasma levels of aPTT, PT and thrombin clotting time (TCT) returned to the normal range in 100%, 97% and 91% after treatment with heparinase, respectively. Plasma samples of patients on coumarin were spiked with 2IU heparin/ml (n = 40) and were treated with heparinase. aPTT returned to baseline levels in 97.5%, PT in 99% and TCT in 69% of the samples. Plasma samples of patients receiving both heparin and coumarin were treated with heparinase (n = 18). aPTT and TCT values were shortened substantially and displayed the prolongation due to the effect of oral anticoagulants. PT values in these patients were also shortened. Freezing of plasma samples after treatment with heparinase resulted in a prolongation of the coagulation times in 15% of PT, 7% of aPTT and not of TCT values. The results show that treatment of plasma samples with heparinase abolishes the effect of unfractionated and low molecular weight heparin in vitro and ex vivo in patients during simultaneous treatment with oral anticoagulants. The use of heparinase may be of significance in patients with concomitant treatment of heparin and oral anticoagulants.

Freezing↗
PubMed1996

Comparison of the relative efficacy and safety of low molecular weight heparin and unfractionated heparin for the treatment of venous thrombosis.

LMWH has been compared with unfractionated heparin in the treatment of venous thrombosis. The results of a pooled analysis studies of hospitalized patients showed a significant reduction of thrombus size, p < 0.001 and in the incidence of recurrent venous thromboembolism, p < 0.001 and of major bleeding p < 0.005 in patients treated with LMWH. The pooled mortality rate at long term follow-up was also found to be lower in LMWH group. Two large randomized trials have been completed in which LMWH was administered subcutaneously on an outpatient basis and compared with the standard approach of unfractionated heparin administered by continuous intravenous infusion in hospital. In both studies the efficacy, safety and mortality in the LMWH and heparin groups were similar.

Adult↗
PubMed1996

New antithrombotics for the treatment of acute and chronic arterial ischemia.

The established antithrombotic agents are effective but they have limitations which have provided opportunities for the development of new antithrombotic compounds. Of these new agents, the antithrombin III-independent thrombin inhibitors and the platelet GPIIb/IIIa receptor antagonists are the most advanced in their development. Other new antithrombotic agents include the antithrombin III-independent factor Xa inhibitors, activated protein C, soluble thrombomodulin and tissue factor pathway inhibitor. Of the GPIIb/IIIa antagonists, the humanized 7E3 antibody and integrin have been evaluated in phase III studies. The 7E3 antibody was effective in preventing both short-term and longer-term complications of coronary angioplasty. The antithrombin III-independent thrombin inhibitors hirudin and hirulog have also been evaluated in phase III studies. The studies with hirudin as an adjuvant to coronary thrombolysis had to be terminated and restarted at lower dosages because of an unacceptable incidence at intracranial hemorrhage and the study with hirulog produced equivocal results.

Acute Disease↗
PubMed1995

Prolonged antithrombin activity of low-molecular-weight heparins. Clinical implications for the treatment of thromboembolic diseases.

BACKGROUND: The mechanism for the efficacy of once- or twice-daily subcutaneous injections of low-molecular-weight heparins (LMWHs) for the treatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies that the antithrombin activity of LMWHs is necessary for their antithrombotic effect is inconsistent with the reported short half-life of the antithrombin activity of LMWHs. Previous pharmacokinetic studies were performed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensitive chromogenic assay. METHODS AND RESULTS: We performed a pharmacokinetic study to compare the relative half-lives of prophylactic and therapeutic doses of LMWHs assessing antithrombin activity with both the chromogenic and a more sensitive assay (plasma thrombin neutralization assay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadroparin (7500 and 10,000 ICU and 225 and 450 ICU/kg) were administered subcutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose-dependent peak activity was found for both antifactor Xa and antithrombin activities. Disappearance time of these activities after the highest dose of both LMWHs was longer than 16 hours. Overall mean antifactor Xa activity half-life was 4.6 hours. Overall mean antithrombin activity half-life was longer than 4 hours. CONCLUSIONS: Our results provide an explanation for the effectiveness of LMWHs administered either once or twice daily. High and sustained plasma antithrombin activity is achieved when LMWHs are administered in therapeutic doses used in contemporary trials with only a moderate prolongation of the aPTT.

Adult↗
PubMed1995

Antiphospholipid antibodies and venous thromboembolism.

The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus erythematosus who have venous thromboembolism (VTE) in unknown. Limited evidence suggests that there is an association between the presence of APLA and both initial and recurrent episodes of VTE and that patients with APLA and VTE are resistant to warfarin therapy. Unselected patients with a first episode of clinically suspected deep vein thrombosis or pulmonary embolism were evaluated with objective tests for VTE and with laboratory tests for APLA; the latter included tests for the lupus anticoagulant (LA) and anticardiolipin antibodies (ACLA). Patients with VTE were treated with anticoagulant therapy and observed during and after discontinuation of anticoagulants for symptomatic recurrence of VTE. There was a strong association between LA and VTE (odds ratio, 9.4; 95% confidence interval [CI], 2.1 to 46.2) and 9 to 65 (14%; 95% CI, 7% to 25%) patients with VTE had LA. There was no association between the presence of ACLA and VTE (odds ratio, 0.7; 95%CI, 0.3 to 1.7) because of the high frequency of positive ACLA assays in patients without VTE. None of the 16 patients with VTE and APLA developed recurrent VTE while receiving warfarin therapy. There was no difference in rates of recurrent VTE in patients with or without APLA after anticoagulant therapy was discontinued. The strong association between LA and VTE suggests that testing for LA in patients with VTE is useful. The measurement of ACLA in patients with VTE has no clinical usefulness because the results are abnormal in a high proportion of patients without VTE. Although the presence of APLA in patients with VTE was not associated with resistance to a conventional intensity of warfarin or an increased risk of recurrent VTE after discontinuation of warfarin, a larger study should address these issues in a subgroup of patients with VTE and LA.

Adolescent↗
PubMed1995

The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria.

Osteoporosis is a well-recognized complication of long-term heparin use. However, the mechanisms by which heparin can influence bone metabolism are unclear. We report here that unfractionated heparin stimulates the process of bone resorption and that the low molecular weight heparins (LMWHs), enoxaparin, fragmin, logiparin, and ardeparin produce significantly less calcium loss than unfractionated heparin. To assess calcium loss from bone, we quantified the release of 45Ca into the culture medium of fetal rat calvaria. 45Ca release was increased in a dose-dependent manner by the addition of either unfractionated heparin or the LMWHs; but more than 50-fold higher LMWH concentrations were required to obtain an equivalent effect to unfractionated heparin. Thus, at concentration > or = 2 micrograms/mL (0.35 anti-Xa units/mL), unfractionated heparin stimulated 45Ca release 1.53 +/- 0.06 fold. 45Ca release was increased to a similar extent by the addition of either 10(-7) mol/L parathyroid hormone (PTH) or 10(-6) mol/L 1,25 dihydroxyvitamin D3 (1,25 Vit D3). In contrast to unfractionated heparin, LMWH concentrations > or = 100 micrograms/mL (> or = 14.0 anti-Xa units/mL) were required before maximum isotope release was observed. At concentrations well above therapeutic levels, the LMWHs stimulated 45Ca release by only 1.25 /+- 0.01-fold. Heparins with high and low antithrombin III affinities stimulated 45Ca release equally well. Both size and sulfation were found to be major determinants of heparin's ability to promote isotope release. Thus, the ability of defined heparin fragments to stimulate 45Ca release correlated with their molecular weight, and after N-desulfation the ability of heparin to induce isotope release was greatly diminished. Dermatan sulfate had no effect on 45Ca release. We conclude that size and sulfation are major determinants of heparin's ability to promote bone resorption and that the risk of heparin-induced osteoporosis may be reduced by the use of LMWH preparations.

Animals↗
PubMed1995

Accuracy of clinical assessment of deep-vein thrombosis.

The clinical diagnosis of deep-vein thrombosis is generally thought to be unreliable. From experience, we hypothesised that this widely held view might be incorrect. We developed a clinical model and prospectively tested its ability in three tertiary care centres to stratify symptomatic outpatients with suspected deep-vein thrombosis into groups with high, moderate, or low probability groups of deep-vein thrombosis. We evaluated our clinical model in combination with venous ultrasonography to determine the potential for an improved and simplified diagnostic approach in patients with suspected deep-vein thrombosis. All patients were clinically assessed to determine the probability for deep-vein thrombosis before they had ultrasonography and venography. All tests were performed and interpreted by independent observers. In 529 patients, the clinical model predicted prevalence of deep-vein thrombosis in the three categories: 85% in the high pretest probability category, 33% in the moderate, and 5% in the low category. There was no statistical difference in the performance of the model in the three centres. The model demonstrated excellent interobserver reliability (Kappa = 0.85). There were important differences with ultrasonography between the high and low pretest probability groups for both positive predictive values (100% (95% CI, 94-100%) vs (63% [35-85%], respectively). Thus, use of the clinical model combined with ultrasonography would decrease the number of false positive and negative diagnosis if venography were done when the ultrasound result and pretest probability were discordant. The diagnostic process could be simplified by excluding those patients with low pretest probability and normal ultrasound results from serial testing.

Decision Trees↗
PubMed1995

Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.

BACKGROUND: Heparin-induced thrombocytopenia, defined by the presence of heparin-dependent IgG antibodies, typically occurs five or more days after the start of heparin therapy and can be complicated by thrombotic events. The frequency of heparin-induced thrombocytopenia and of heparin-dependent IgG antibodies, as well as the relative risk of each in patients given low-molecular-weight heparin, is unknown. METHODS: We obtained daily platelet counts in 665 patients in a randomized, double-blind clinical trial comparing unfractionated heparin with low-molecular-weight heparin as prophylaxis after hip surgery. Heparin-induced thrombocytopenia was defined as a decrease in the platelet count below 150,000 per cubic millimeter that began five or more days after the start of heparin therapy, and a positive test for heparin-dependent IgG antibodies. We also tested a representative subgroup of 387 patients for heparin-dependent IgG antibodies regardless of their platelet counts. RESULTS: Heparin-induced thrombocytopenia occurred in 9 of 332 patients who received unfractionated heparin and in none of 333 patients who received low-molecular-weight heparin (2.7 percent vs. 0 percent; P = 0.0018). Eight of the 9 patients with heparin-induced thrombocytopenia also had one or more thrombotic events (venous in 7 and arterial in 1), as compared with 117 of 656 patients without heparin-induced thrombocytopenia (88.9 percent vs. 17.8 percent; odds ratio, 36.9; 95 percent confidence interval, 4.8 to 1638; P < 0.001). In the subgroup of 387 patients, the frequency of heparin-dependent IgG antibodies was higher among patients who received unfractionated heparin (7.8 percent, vs. 2.2 percent among patients who received low-molecular-weight heparin; P = 0.02). CONCLUSIONS: Heparin-induced thrombocytopenia, associated thrombotic events, and heparin-dependent IgG antibodies are more common in patients treated with unfractionated heparin than in those treated with low-molecular-weight heparin.

Confidence Intervals↗
PubMed1995

A novel and rapid whole-blood assay for D-dimer in patients with clinically suspected deep vein thrombosis.

BACKGROUND: The clinical utility of using a novel whole blood assay for D-dimer (SimpliRED), alone or in combination with impedance plethysmography (IPG), was investigated in a two-center, prospective cohort study of 214 consecutive patients with clinically suspected deep vein thrombosis (DVT). METHODS AND RESULTS: All patients underwent the SimpliRED D-dimer assay, contrast venography, and IPG. According to the results of venography, 43 patients had proximal DVT (popliteal and/or more proximal veins), 10 had isolated calf DVT, and 161 had DVT ruled out. The D-dimer had a sensitivity of 93% for proximal DVT and of 70% for calf DVT, an overall specificity of 77%, and a negative predictive value of 98% for proximal DVT. The sensitivity and specificity of IPG for proximal DVT were 67% and 96%, respectively. When analyzed in combination with the IPG results, it was determined that (1) the combination of a negative D-dimer and a normal IPG had a negative predictive value of 97% for all DVT and of 99% for proximal DVT and occurred in 58% of patients (likelihood ratio, 0.1) and (2) the combination of a positive D-dimer and an abnormal IPG had a positive predictive value of 93% for any DVT and of 90% for proximal DVT and occurred in 14% of patients (likelihood ratio, 42.6). When the D-dimer and IPG results were discordant, it was not possible to exclude or diagnose DVT reliably; discordant results occurred in 28% of patients. CONCLUSIONS: The SimpliRED D-dimer assay, which can be performed and interpreted at the bedside within 5 minutes, has great potential in patients with clinically suspected DVT, especially for ruling out DVT, and is complementary to IPG. The assay should be evaluated in large clinical management studies.

Agglutination Tests↗
PubMed1995

Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis.

BACKGROUND: An intravenous course of unfractionated heparin adjusted on the basis of the activated partial thromboplastin time is the initial treatment of choice for most patients with venous thromboembolism. Recently introduced low-molecular-weight heparin preparations can be administered subcutaneously, once or twice daily, without laboratory monitoring. We quantitatively assessed the relative efficacy and safety of low-molecular-weight heparin vs standard heparin for the initial treatment of deep venous thrombosis. METHODS: English-language reports of randomized trials were identified through a MEDLINE search (1984 through 1994) and a complementary extensive manual search. Reasons for exclusion from the analysis were no heparin dosage adjustments, the lack of use of objective tests for deep venous thrombosis, duplicate reports, preliminary reports of data later presented in full, dose-ranging studies that used higher doses of low-molecular-weight heparin than are currently in use, and the failure to provide blind end-point assessment. We assessed the incidence of symptomatic recurrent venous thromboembolic disease, the incidence of clinically important bleeding, and mortality. RESULTS: Ten of the 19 identified trials satisfied the predetermined criteria. The relative risk reductions for symptomatic thromboembolic complications (53% [95% confidence interval, 18% to 73%]), clinically important bleeding (68% [95% confidence interval, 31% to 85%]), and mortality (47% [95% confidence interval, 10% to 69%]) were all statistically significantly in favor of low-molecular-weight heparin. CONCLUSIONS: Low-molecular-weight heparins administered subcutaneously in fixed doses adjusted for body weight and without laboratory monitoring are more effective and safer than adjusted-dose standard heparin. Since low-molecular-weight heparins may not be interchangeable and the conclusions of our meta-analysis are based mainly on the findings of three trials that used two different low-molecular-weight heparins, definitive randomized controlled trials for the other low-molecular-weight heparins are required.

Hemorrhage↗
PubMed1995

Deep vein thrombosis: recovery or recurrence?

As many as two thirds of patients with new symptoms after documented DVT have postphlebitic syndrome, not DVT. Noninvasive imaging is central to the differentiation so that unnecessary anticoagulation therapy can be avoided. Recent changes in heparin and warfarin protocols for DVT are also outlined.

Bandages↗
PubMed1995

Maximizing the benefits of thrombolytic therapy for acute myocardial infarction.

Thrombolytic therapy is a huge advance in the management of acute myocardial infarction (AMI). The results of large clinical trials over the past 9 years have unequivocally demonstrated its benefit: of every 1000 patients treated 30 will be saved, at a cost of two cases of nonfatal cerebral hemorrhage and seven of noncerebral major hemorrhage. The concurrent use of acetylsalicylic acid increases the benefit of thrombolytic therapy. Sales figures for thrombolytic agents indicate that their use in Canada is less than optimal and lags behind that in several European countries. Major educational efforts are needed to promote awareness of the efficacy of thrombolytic therapy and of optimal approaches for maximizing its potential benefit for patients with AMI.

Clinical Trials as Topic↗
PubMed1995

Exon skipping by overexpression of a Drosophila heterogeneous nuclear ribonucleoprotein in vivo.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are abundant RNA-binding proteins that are implicated in splicing regulation. Here we investigate the role of a Drosophila hnRNP in splicing regulation in living animals. We find that overexpression of the Drosophila hnRNP HRB98DE leads to skipping of all internal exons in the Drosophila dopa decarboxylase (Ddc) pre-mRNA in vivo. These results indicate that HRB98DE has a splicing activity that promotes use of terminal splice sites. The effect of excess HRB98DE on Ddc splicing is transient, even though high levels of HRB98DE persist for at least 24 hr. This suggests that Drosophila larvae can induce a compensating mechanism to counteract the effects of excess HRB98DE.

Animals↗