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Biomedical subjects

R D Hull

Publications and source records attributed to R D Hull.

At least 19 recordsLinked to original sources
PubMed2001

Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review.

PURPOSE: Evidence-based medicine guidelines based on venographic end points recommend in-hospital prophylaxis with low-molecular-weight heparin (LMWH) in patients having elective hip surgery. Emerging data suggest that out-of-hospital use may offer additional protection; however, uncertainty remains about the risk-benefit ratio. To provide clinicians with a practical pathway for translating clinical research into practice, we systematically reviewed trials comparing extended out-of-hospital LMWH prophylaxis versus placebo. DATA SOURCES: Studies were identified by 1) searching PubMed, MEDLINE, and the Cochrane Library Database for reports published from January 1976 to May 2001; 2) reviewing references from retrieved articles; 3) scanning abstracts from conference proceedings; and 4) contacting pharmaceutical companies and investigators of the original reports. STUDY SELECTION: Randomized, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty. DATA EXTRACTION: Two reviewers extracted data independently. Reviewers evaluated study quality by using a validated four-item instrument. DATA SYNTHESIS: Six of seven original articles met the defined inclusion criteria. The included studies were double-blind trials that used proper randomization procedures. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of deep venous thrombosis (placebo rate, 150 of 666 patients [22.5%]; relative risk, 0.41 [95% CI, 0.32 to 0.54; P < 0.001]), proximal venous thrombosis (placebo rate, 76 of 678 patients [11.2%]; relative risk, 0.31 [CI, 0.20 to 0.47; P < 0.001]), and symptomatic venous thromboembolism (placebo rate, 36 of 862 patients [4.2%]; relative risk, 0.36 [CI, 0.20 to 0.67; P = 0.001]). Major bleeding was rare, occurring in only one patient in the placebo group. CONCLUSIONS: Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic deep venous thrombosis and symptomatic venous thromboembolism. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery.

Aftercare↗
PubMed2001

Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review.

BACKGROUND: Perioperative and postoperative venous thrombosis are common in patients undergoing elective hip surgery. Prophylactic regimens include subcutaneous low-molecular-weight heparin 12 hours or more before or after surgery and oral anticoagulants. Recent clinical trials suggest that low-molecular-weight heparin initiated in closer proximity to surgery is more effective than the present clinical practice. We performed a systematic review of the literature to assess the efficacy and safety of low-molecular-weight heparin administered at different times in relation to surgery vs oral anticoagulant prophylaxis. METHODS: Reviewers (A.F.M. and S.M.M.) identified studies by searching MEDLINE, reviewing references from retrieved articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies. Randomized trials comparing low-molecular-weight heparin administered at different times relative to surgery with oral anticoagulants in patients undergoing elective hip arthroplasty, evaluated using contrast phlebography, were selected. Two reviewers (A.F.M. and S.M.M.) extracted data independently. RESULTS: The literature review identified 4 randomized trials meeting predefined inclusion criteria. The results indicate that low-molecular-weight heparin initiated in close proximity to surgery resulted in absolute risk reductions of 11% to 13% for deep vein thrombosis, corresponding to relative risk reductions of 43% to 55% compared with oral anticoagulants. Low-molecular-weight heparin initiated 12 hours before surgery or 12 to 24 hours postoperatively was not more effective than oral anticoagulants. Low-molecular-weight heparin initiated postoperatively in close proximity to surgery at half the usual dose was not associated with a clinically or statistically significant increase in major bleeding rates (P =.16). CONCLUSIONS: The timing of initiating low-molecular-weight heparin significantly influences antithrombotic effectiveness. The practice of delayed initiation of low-molecular-weight heparin prophylaxis results in suboptimal antithrombotic effectiveness without a substantive safety advantage.

Administration, Oral↗
PubMed2001

Mining the chemical quarry with joint chemical probes: an application of latent semantic structure indexing (LaSSI) and TOPOSIM (Dice) to chemical database mining.

In this study we use a novel similarity search technique called latent semantic structure indexing (LaSSI) with joint chemical probes as queries to mine the MDL drug data report database. LaSSI is based on latent semantic indexing developed for searching textual databases. We use atom pair and topological torsion descriptors in our calculations. The results obtained with LaSSI are compared with another in-house similarity search technique TOPOSIM. The results from the similarity searches using joint chemical probes are significantly better than searches using single chemical probes for both LaSSI and TOPOSIM. The selected molecules are closely related in activity to their queries and are ranked among the top 300 scoring molecules of the 82 860 entries in the database. Our implementation of LaSSI is very fast and efficient in finding active compounds. The results also show that LaSSI consistently retrieves more diverse chemical structures representative of the joint chemical probes in comparison to TOPOSIM. The use of multimolecule topological probes to identify compounds complements the use of searching databases with 3D pharmacophore hypotheses.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Chemical similarity searches using latent semantic structural indexing (LaSSI) and comparison to TOPOSIM.

Similarity searches based on chemical descriptors have proven extremely useful in aiding large-scale drug screening. Here we present results of similarity searching using Latent Semantic Structure Indexing (LaSSI). LaSSI uses a singular value decomposition on chemical descriptors to project molecules into a k-dimensional descriptor space, where k is the number of retained singular values. The effect of the projection is that certain descriptors are emphasized over others and some descriptors may count as partially equivalent to others. We compare LaSSI searches to searches done with TOPOSIM, our standard in-house method, which uses the Dice similarity definition. Standard descriptor-based methods such as TOPOSIM count all descriptors equally and treat all descriptors as independent. For this work we use atom pairs and topological torsions as examples of chemical descriptors. Using objective criteria to determine how effective one similarity method is versus another in selecting active compounds from a large database, we find for a series of 16 drug-like probes that LaSSI is as good as or better than TOPOSIM in selecting active compounds from the MDDR database, if the user is allowed to treat k as an adjustable parameter. Typically, LaSSI selects very different sets of actives than does TOPOSIM, so it can find classes of actives that TOPOSIM would miss.

Algorithms↗
PubMed2001

Latent semantic structure indexing (LaSSI) for defining chemical similarity.

A novel method for computing chemical similarity from chemical substructure descriptors is described. This new method, called LaSSI, uses the singular value decomposition (SVD) of a chemical descriptor-molecule matrix to create a low-dimensional representation of the original descriptor space. Ranking molecules by similarity to a probe molecule in the reduced-dimensional space has several advantages over analogous ranking in the original descriptor space: matching latent structures is more robust than matching discrete descriptors, choosing the number of singular values provides a rational way to vary the "fuzziness" of the search, and the reduction in the dimensionality of the chemical space increases searching speed. LaSSI also allows the calculation of the similarity between two descriptors and between a descriptor and a molecule.

Algorithms↗
PubMed2001

Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patients undergoing elective hip surgery.

Administration of low-molecular-weight heparin prophylaxis in elective hip implant patients commonly begins 12 h preoperatively in European practices to optimize effectiveness, and 12 to 24 h postoperatively in North American practices to optimize safety. A meta-analysis comparing these two treatment regimes revealed that preoperative initiation demonstrated greater efficacy and superior safety for patients (10.0% rate of total deep-vein thrombosis vs. 15.3%, P = .023). In addition to the pre/postsurgical debate, proximity of initiation of low-molecular-weight heparin in relation to surgery is an issue of critical importance. Recent studies revealed that beginning therapy immediately within 2 h preoperatively or 6 h postoperatively dramatically decreased the risk of venous thrombosis. An investigation of low-molecular-weight heparin prophylaxis initiated 2 h before elective hip surgery or approximately 6 h after surgery compared with warfarin sodium revealed that total and proximal deep-vein thrombosis rates were reduced in patients receiving low-molecular-weight heparin compared with warfarin. The frequencies of deep-vein thrombosis for patients receiving preoperative and postoperative dalteparin vs. warfarin for all deep-vein thrombosis were 36 of 337 (10.7%, P < .001) and 44 of 336 (13.1%, P < .001) vs. 81 of 338 (24.0%); and for proximal deep-vein thrombosis were 3 of 354 (0.8%, P = .035) and 3 of 358 (0.8%, P = .033) vs. 11 of 363 (3.0%). Relative risk reductions for the dalteparin groups vs. warfarin ranged from 45% to 72%. In this case, low-molecular-weight heparin administered in close proximity to surgery provided superior efficacy over warfarin. Major bleeding was significantly increased with the preoperative regimen but not the postoperative regimen.

Arthroplasty, Replacement, Hip↗
PubMed2001

Cost-effectiveness of currently accepted strategies for pulmonary embolism diagnosis.

Improvements in the methods of clinical trials combined with the use of objective tests to detect venous thrombosis have enhanced the clinician's ability to diagnose pulmonary embolism and venous thrombosis (venous thromboembolism). The authors updated a previous cost-effectiveness analysis of the commonly recommended strategies for pulmonary embolism diagnosis and management to reflect current clinical practice. Two criteria of effectiveness were used: correct identification of venous thromboembolism and correct identification of venous thromboembolism and correct identification of patients for whom treatment was unnecessary. The cost of each diagnostic alternative was defined as the direct cost of administering the diagnostic tests plus the treatment costs associated with a positive test result. A strategy based on the combined use ofventilation-perfusion lung scanning, serial ultrasonography, cardiorespiratory evaluation, and pulmonary angiography was the most cost-effective. This strategy also necessitated pulmonary angiography in the fewest number of patients. The safety of this strategy relates to two important biologic concepts: 1) local extension of submassive pulmonary embolism in the lung is not an important cause of morbidity or mortality in patients with adequate cardiorespiratory reserve, and 2) in most patients, proximal vein thrombi of the lower extremities are the source of recurrent pulmonary embolism.

Cost-Benefit Analysis↗
PubMed2001

Development of a National Occupational Exposure Survey and Database associated with NIOSH hazard surveillance initiatives.

NIOSH pioneered hazard surveillance in the workplace by designing and conducting the 1972 to 1974 National Occupational Hazard Survey (NOHS), the 1981 to 1983 National Occupational Exposure Survey (NOES), and the 1984 to 1989 National Occupational Health Survey of Mining (NOHSM). The databases developed from these three on-site surveys represent unique resources for associating potential chemical, physical and biological agents with industries and occupational groups. The data have been a primary source of information for NIOSH, regulatory agencies, health professionals, researchers, and labor organizations in establishing priorities for prevention strategies that include medical and engineering interventions, development of occupational standards, and the identification of research needs. Recognizing that the data from these surveys are becoming dated, a multidisciplinary team comprising members from various NIOSH research divisions was established to develop a hazard surveillance strategy for the Institute, including options for a national hazard surveillance survey and database. The proposed new hazard survey builds on lessons learned from the previous surveys, seeks opportunities to incorporate existing data from other sources, expands the scope of industries and hazards, and takes advantage of advances in data gathering, processing and dissemination technology. This article presents current considerations and recommendations for a new hazard survey and database.

Data Collection↗
PubMed2001

Orally active heparin and low-molecular-weight heparin.

The heparins, (unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH)) given by subcutaneous or intravenous injection have been used extensively in the prevention and treatment of both venous and arterial thromboembolic disorders. The increasing use of the heparins, LMWHs in particular, in the out of hospital setting has stimulated interest in the development of orally absorbable antithrombotic agents that require little or no monitoring, and this includes the heparins. UFH or LMWH delivered orally has been shown to have an antithrombotic effect in animal thrombosis models although there is little change in plasma coagulation tests. The addition of a simple organic chemical N -(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) to UFH markedly enhances its absorption. A phase II study in patients undergoing total hip replacement indicated that SNAC heparin in two different doses was as effective and safe as UFH given subcutaneously. A phase III clinical trial comparing two doses of SNAC heparin given orally with LMWH by subcutaneous injection for the prevention of venous thromboembolism in patients undergoing total hip replacement is currently underway.

Administration, Oral↗
PubMed2001

Dalteparin sodium.

Dalteparin sodium (Fragmin, Pharmacia Corporation) is a low molecular weight heparin (LMWH) with a mean molecular weight of approximately 5000 Da. As with the other LMWHs, dalteparin sodium has certain advantages over unfractionated heparin (UFH), most important of which are improved bio-availability by sc. injection, a prolonged antithrombotic activity which is highly correlated with body weight permitting the o.d. administration of the drug. Dalteparin sodium has been subjected to a large number of well-designed randomised clinical trials for the prevention and treatment of thrombotic disorders. Based on data from the randomised clinical trials, dalteparin sodium has been approved internationally for a wide spectrum of clinical indications (e.g., prevention of thromboembolic events after surgery). Dalteparin sodium has also been studied in randomised controlled trials in the maintenance of graft patentcy following peripheral vascular surgery, in place of warfarin for the long-term treatment of patients presenting with deep vein thrombosis (DVT), in the prevention of upper extremity thrombosis in patients with indwelling portacath devices and in pregnant patients with a history of previous venous thromboembolism with or without thrombophilia. Dalteparin sodium has been compared with heparin for the prevention of thrombotic complications during haemodyalisis and haemofiltration. These studies have shown promising results but further work is required before dalteparin sodium can be recommended for these indications.

Animals↗
PubMed2001

Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis.

OBJECTIVES: We conducted population anticoagulant pharmacodynamic analysis for patients administered the low-molecular weight heparin tinzaparin. METHODS: Data from 425 patients (2,631 observations) who participated in 2 Phase III clinical studies were utilized in an analysis based on a pharmacodynamic structural model of anti-Xa activity using non-linear mixed effects modeling techniques. Anti-Xa activity from patients participating in a multicenter, randomized, double-blind clinical trial comparing intravenous once daily subcutaneous tinzaparin (175 IU/kg) with heparin for the treatment of deep vein thrombosis (DVT) was first examined using a 2-compartment model with first-order absorption and endogenous anti-Xa activity. Covariates included renal function, body weight, age, gender, race, obesity, concomitant administration of warfarin, and diabetes. RESULTS: The population estimates and 90% confidence intervals (CI) for oral clearance (CL) and apparent volume of distribution of the plasma compartment (Vc) were 0.0176 l/h/kg (CI = 0.012-0.023) and 0.098 l/kg (CI = 0.088 - 0.109), respectively. The elimination half-life was 3.9 h (CI = 2.5-5.2). These estimates are similar to findings in healthy volunteers. The inter-patient variability in clearance was related to plasma creatinine and percent above ideal body weight. Clearance decreased by 22% for patients with severe renal function impairment (creatinine clearance < 30 ml/min), and by about 25% in obese patients (BMI > 30 kg/m2). CONCLUSIONS: Changes of these magnitudes were not clinically important in pooled clinical trial safety and efficacy analyses. Body weight was not a significant covariate in the model supporting the observations in earlier well-defined trials, where tinzaparin was dosed on a weight basis (lU/kg). Clearance was not influenced by age, race or gender. The same model was applied to data obtained from a prospective, randomized, double-blind clinical trial comparing tinzaparin (4,500 IU) to enoxaparin (40 mg) once daily in patients undergoing total hip replacement. Model parameters were similar to those previously obtained supporting the extension of these results across dose and indication. Population analysis in patients with disease and heterogeneity indicated similar pharmacodynamics as in volunteers, supporting weight-based dosing and identified the dependence of clearance on obesity and severe renal function, although the magnitude of these effects are probably not clinically significant.

Adult↗
PubMed2000

Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators.

BACKGROUND: Based on the current understanding that venous thrombosis starts perioperatively, administration of just-in-time low-molecular-weight heparin immediately before or in close proximity after hip arthroplasty may be more effective than usual clinical practice. METHODS: We performed a randomized, double-blind trial comparing subcutaneous dalteparin sodium given once daily immediately before or early after surgery with the use of postoperative warfarin sodium in 1472 patients undergoing elective hip arthroplasties. The primary end point was deep vein thrombosis detected using contrast venography performed after surgery (mean, 5. 7 days) in each group. RESULTS: The frequencies of deep vein thrombosis for patients with interpretable venograms receiving preoperative and postoperative dalteparin for all deep vein thrombosis were 36 (10.7%) of 337 (P<.001) and 44 (13.1%) of 336 (P<.001), respectively, vs 81 (24.0%) of 338 for warfarin; for proximal deep vein thrombosis, 3 (0.8%) of 354 (P =.04) and 3 (0.8%) of 358 (P =.03), respectively, vs 11 (3.0%) of 363. Relative risk reductions for the dalteparin groups ranged from 45% to 72%. Symptomatic thrombi were less frequent in the preoperative dalteparin group (5/337 patients [1.5%]) vs the warfarin group (15/338 patients [4.4%]) (P =.02). Serious bleeding was similar among groups. Increased major bleeding at the surgical site was observed for patients receiving preoperative dalteparin vs warfarin (P =.01). CONCLUSIONS: A modified dalteparin regimen in close proximity to surgery resulted in substantive risk reductions for all and proximal deep vein thrombosis, compared with warfarin therapy. Such findings have not been observed with low-molecular-weight heparin therapy commenced 12 hours preoperatively or 12 to 24 hours postoperatively vs oral anticoagulants. Increased major but not serious bleeding occurred in patients receiving preoperative dalteparin. Dalteparin therapy initiated postoperatively provided superior efficacy vs warfarin without significantly increased overt bleeding.

Anticoagulants↗
PubMed2000

Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators.

BACKGROUND: No randomized trials have directly evaluated the need for extended out-of-hospital thromboprophylaxis for patients who have hip arthroplasty in the United States or Canada. The uncertainty as to the need for extended prophylaxis in North American patients is complicated by early hospital discharge, resulting in a short thromboprophylaxis interval. METHODS: To resolve this uncertainty, we performed a randomized double-blind trial in 569 patients who underwent hip arthroplasty comparing the use of dalteparin sodium started immediately before surgery or early after surgery and extended out-of-hospital to an overall interval of 35 days with the use of warfarin sodium in-hospital and placebo out-of-hospital. RESULTS: For patients with interpretable venograms in the preoperative, postoperative, and combined dalteparin groups, new proximal vein thrombosis out-of-hospital was observed in 1.3%, 0. 7% (P =.04), and 1.0% (P =.02) of patients, respectively, compared with 4.8% in the in-hospital warfarin/out-of-hospital placebo group. The respective overall cumulative frequencies of all deep vein thrombosis were 30 (17.2%) of 174 patients (P<.001), 38 (22.2%) of 171 (P =.003), and 68 (19.7%) of 345 (P<.001) in the dalteparin groups compared with 69 (36.7%) of 188 for the in-hospital warfarin/out-of-hospital placebo group. For proximal deep vein thrombosis, the respective frequencies were 5 (3.1%) of 162 (P =.02), 3 (2.0%) of 151 (P =.007), and 8 (2.6%) of 313 (P =.002) compared with 14 (9.2%) of 153. No major bleeding occurred during the extended prophylaxis interval. CONCLUSIONS: Extended dalteparin prophylaxis resulted in significantly lower frequencies of deep vein thrombosis compared with in-hospital warfarin therapy. Despite in-hospital thromboprophylaxis, patients having hip arthroplasty in the United States and Canada remain at moderate risk out-of-hospital. The number needed to treat provides a public health focus; only 24 to 28 patients require extended prophylaxis to prevent 1 new out-of-hospital proximal vein thrombosis. Recent studies demonstrate that asymptomatic deep vein thrombi cause the postphlebitic syndrome; thus, extended out-of-hospital prophylaxis will lessen the burden to both the patient and society.

Anticoagulants↗