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Biomedical subjects

R D Hull

Publications and source records attributed to R D Hull.

At least 55 records · Page 3Linked to original sources
PubMed1998

Prophylaxis of deep venous thrombosis and pulmonary embolism. Current recommendations.

Pulmonary embolism is responsible for approximately 150,000 to 200,000 deaths per year in the United States. Venous thromboembolism usually occurs as a complication in patients who are sick and hospitalized, but it may also affect ambulant and otherwise healthy individuals. Many patients who die from pulmonary embolism succumb suddenly or within 2 hours after the acute event (i.e., before therapy can be initiated or take effect). Therefore, prevention is the key to reducing death and morbidity from venous thromboembolism. Effective and safe prophylactic measures against venous thromboembolism are now available for most high-risk patients. This article highlights practical approaches to the prevention of venous thromboembolism.

Humans↗
PubMed1998

Unfractionated and low-molecular-weight heparin. Comparisons and current recommendations.

Intravenous heparin followed by warfarin has been the classical anticoagulant therapy of acute venous thromboembolism for the past 30 years. In recent years a number of low-molecular-weight heparins have become available for clinical trials. These agents have a number of advantages over unfractionated heparin and are now being used internationally for the prevention and treatment of venous thromboembolism. Low-molecular-weight heparin will undoubtedly replace intravenous unfractionated heparin not only in the treatment of venous thromboembolism but in other conditions where heparin therapy is indicated. Whether or not the low-molecular-weight heparins can decrease or eliminate some of the complications of unfractionated heparin will depend on the outcome of future clinical trials.

Anticoagulants↗
PubMed1998

Thrombophilia: disorders predisposing to venous thromboembolism.

Venous thromboembolism continues to present a challenge to clinicians. Over the years, a number of risk factors which predispose to venous thromboembolism have been identified, and these risk factors are taken into account in the formulation of recommendations for the prevention and treatment of these disorders. In more recent years, there have been major advances in our understanding of congenital or acquired defects that predispose to thrombosis leading to these so-called acquired or inherited forms of thrombophilia. The list of acquired forms of thrombophilia now includes anti-thrombin, protein C, protein S, activated protein C resistance, the prothrombin 20210A mutant, homocysteinemia and a number of rare defects which either enhance coagulation or interfere with fibrinolysis. In spite of these advances, there are numerous families with thrombophilia in whom none of the known defects can be demonstrated. The challenge for the future is to discover some of these as yet unknown factors and to determine the most appropriate methods for the prevention and treatment of venous thromboembolism in susceptible individuals with thrombophilia.

Activated Protein C Resistance↗
PubMed1998

Heparin and low-molecular-weight heparin in the treatment of venous thromboembolism.

Venous thromboembolism (deep vein thrombosis and pulmonary embolism) continues to constitute a major clinical challenge. Effective and safe prophylactic measures against venous thromboembolism are now available for most high risk patients. In spite of this, pulmonary embolism is responsible for approximately 150,000 to 200,000 deaths per year in the United States alone. Over the past 20 years, based on a number of high quality (Level I) clinical trials, patterns of practice with respect to the treatment of venous thromboembolism have changed dramatically. The standard treatment of venous thromboembolism has been the use of unfractionated heparin by continuous intravenous infusion, with laboratory monitoring using the activated partial thromboplastin time (APTT), with warfarin starting on day 1 or 2 and continued for 3 months. Unfractionated heparin has withstood the test of time and has been shown to be safe and effective in preventing recurrent venous thromboembolism and death in numerous clinical trials. The response of individual patients to heparin is highly variable, requiring frequent laboratory monitoring. Heparin has a number of other troublesome side effects including bleeding, heparin-induced thrombocytopenia and osteoporosis. The low-molecular-weight heparins have a number of advantages over unfractionated heparin. In particular, their increased bio-availability and prolonged half-life permit once daily subcutaneous injections and their predictable antithrombotic response based on body weight permits treatment without laboratory monitoring. Low-molecular-weight heparin in therapeutic doses causes less bleeding than unfractionated heparin and evidence is accumulating that the incidence of heparin-induced thrombocytopenia and osteoporosis are decreased as well. In individual clinical trials and meta-analyses, low-molecular-weight heparin treatment results in decreased recurrent thromboembolism, major bleeding and death when compared with unfractionated heparin in the treatment of deep vein thrombosis and pulmonary embolism. These agents have also been shown to be both effective and safe for the out-of-hospital treatment of venous thrombosis. Therefore, in many countries, low-molecular-weight heparin has replaced unfractionated heparin for the treatment of venous thromboembolism.

Anticoagulants↗
PubMed1998

The economic impact of treating deep vein thrombosis with low-molecular-weight heparin: outcome of therapy and health economy aspects.

Subcutaneous low-molecular-weight heparin (LMWH) is at least as safe and effective as classical intravenous heparin therapy for the treatment of proximal vein thrombosis. Anticoagulant monitoring and intravenous administration are not required with LMWH treatment, therefore this therapy may offer economic advantages. An economic evaluation of these therapeutic approaches was performed comparing the costs and effectiveness. The evaluation was aimed at helping decision-makers to maximize the health of the population served, subject to available resources. The American-Canadian Thrombosis Study was a multicentre, randomized, double-blind clinical trial that compared treatment by initial continuous intravenous infusion of heparin (followed by 3 months of warfarin therapy) with a once-daily dose of subcutaneous LMWH, tinzaparin sodium (followed by 3 months of warfarin treatment) in patients with acute proximal deep vein thrombosis. In the LMWH-treated group, the cost incurred for 100 patients was $399,403 (Canadian) or $335,687 (US) with a frequency of objectively documented recurrent venous thromboembolism of 2.8%. In the intravenous heparin-treated group, the cost incurred for 100 patients was $ 414,655 (Canadian) or $ 375,836 (US), with a frequency of objectively documented recurrent venous thromboembolism of 6.9%. These results show a cost saving of $ 15,252 (Canadian) or $ 40,149 (US) with the use of LMWH. Multiple sensitivity analyses did not alter the findings of the study which indicated that LMWH therapy is at least as safe and effective but less costly than intravenous heparin treatment. The potential for outpatient therapy in up to 37% of patients who are receiving LMWH would substantially augment the cost-saving. The cost-effectiveness findings presented in this paper are based on the assumption that all costs are covered by a single payer. Outpatient management in many countries will shift the healthcare costs from the healthcare payer to the patient, increasing the economic burden to the patient.

Anticoagulants↗
PubMed1998

Heparin and low-molecular-weight heparin therapy for venous thromboembolism. The twilight of anticoagulant monitoring.

Recent improvements in the methods of clinical trials and the use of accurate objective tests to detect venous thromboembolism have made possible a series of randomized trials to evaluate various treatments for venous thromboembolism. The results of these trials have resolved many of the uncertainties a clinician confronts in selecting an appropriate course of anticoagulant therapy. These trials have shown that the intensity of both initial heparin treatment and long-term anticoagulant therapy must be sufficient to prevent unacceptable rates of recurrence of venous thromboembolism. Patients with proximal deep vein thrombosis who receive inadequate anticoagulant therapy have a risk of clinically evident, objectively documented recurrent venous thromboembolism that approaches 20% to 25%. The need for therapy with heparin and the importance of monitoring blood levels of the effect of heparin have been established. The importance of achieving adequate heparinization was suggested by a nonrandomized trial in 1972 and randomized trials in the 1980s have confirmed this finding. Furthermore, randomized trials have demonstrated the importance of achieving adequate heparinization early in the course of therapy. Unfractionated intravenous heparin has provided an effective therapy for more than half a century, but the need to monitor therapy and establish therapeutic levels is a fundamental problem. It is evident that validated heparin protocols are more successful in establishing adequate heparinization than intuitive ordering by the clinician. However, even with the best of care using a heparin protocol, some patients treated with intravenous heparin will receive subtherapy. In this context, subtherapy reflects a practical limitation of the use of unfractionated heparin, rather than a poor standard of care. Furthermore, it is recognized that the practical difficulties associated with heparin administration are compounded by the substantive practical difficulties of standardizing APTT testing and the therapeutic range. Our findings emphasize the confounding effect that initial heparin treatment has on long-term outcome. In future trials of longterm therapy, it is imperative that the initial therapy is of adequate intensity and duration; failure to administer adequate initial treatment may lead to a poor outcome that is falsely attributed to the long-term therapy under evaluation. Therapy with low-molecular-weight heparin, which does not require monitoring and dose finding, is the likely practical solution to these dilemmas. Based on the experience of difficulties achieving adequate therapy with subcutaneous unfractionated heparin dosing, we administered a low-molecular-weight heparin formulation in a single daily dose, rather than splitting the treatment into 2 equal doses. The initial intensity of therapy was thereby maximized. Therapy with low-molecular-weight heparin proved to be better than therapy with unfractionated heparin.

Animals↗
PubMed1998

Different effects of heparin in males and females.

OBJECTIVE: To determine whether women have a Pharmacological predisposition to bleeding and a worse outcome than men during heparin therapy, in light of recent studies showing that women have a higher risk of bleeding complications following anticoagulant therapy for thrombotic disorders than men. DESIGN: Prospectively planned subgroup analysis of a double-blind randomized study. SETTING: Academic tertiary care hospitals in Hamilton, Ont. PATIENTS: A total of 199 consecutive patients (105 women, 93 men) presenting with proximal deep vein thrombosis. (One patient was not included due to incomplete data). OUTCOME MEASURES: Activated partial thromboplastin time (APTT) values and heparin levels were assessed every 4 to 6 hours after a standard heparin bolus and infusion. The effect of sex on heparin doses and levels was also assessed after stable therapeutic heparin infusions were achieved. RESULTS: The women had higher heparin levels than the men (0.560 [standard error of the mean, SEM 0.056] units/mL v. 0.347 [SEM 0.062] units/mL, p < 0.0001) and higher APTT values (94.9 [SEM 0.50] seconds v. 81.2 [SEM 0.53] seconds, p = 0.0002) 4 to 6 hours after being given the same heparin bolus and infusion doses. After achieving therapeutic APTT values, the women received lower heparin doses than the men (27.9 [SEM 0.24] 1000 units/24 hours v. 34.5 [SEM 0.24] 1000 units/24 hours, p < 0.0001) but had higher heparin levels (0.349 [SEM 0.035] units/mL v. 0.292 [SEM 0.036] units/mL, p = 0.034). The effect of sex was also determined after correcting for the known effects of weight and age on heparin therapy. After adjusting for patient weight, among the women, older women had higher heparin levels but, among the men, there was little effect of age. There were no sex differences with respect to bleeding complications or recurrent thromboembolic disease. CONCLUSION: Women showed alterations in the pharmacokinetics of heparin, which could explain a predisposition to bleeding complications. Under the heparin protocol used in this study, heparin doses were rapidly adjusted, which may explain why rates of bleeding complications and recurrent thromboembolism were similar in men and women. We do not recommend changes in heparin therapy based on these results, but suggest the use of protocols that assess coagulation parameters frequently and then adjust heparin doses rapidly, in order to individualize therapy. Further study is required to determine whether there are sex differences in bleeding complications associated with anticoagulant therapy, and to confirm the altered pharmacokinetics of heparin in women.

Aging↗
PubMed1998

Treatment and prevention of venous thromboembolism.

Where available, low-molecular-weight heparin (LMWH) is the recommended approach for initial management of venous thromboembolism. When unfractionated heparin is administered, one of the cited heparin nomograms should be used to ensure that the heparin dose is sufficient to rapidly produce heparin levels in the therapeutic range for all patients. Because of the varying sensitivities of thromboplastins, each laboratory should correlate the activated partial thromboplastin time results with heparin's therapeutic range, which will correspond to 0.35 to 0.70 U of heparin/ml blood when using the antifactor Xa assay. Constant vigilance and a high level of suspicion are necessary to establish the clinical diagnosis of heparin-induced thrombocytopenia, and to institute appropriate therapy. When administering warfarin therapy, physicians should be aware of the sensitivity of the thromboplastin being used to provide the international normalized ratio (INR). To ensure that the patients are maintained within the target therapeutic range for INR (in most cases 2.0 to 3.0), the INR should be determined frequently, and the warfarin dosage should then be adjusted appropriately. Patients with an acute episode of venous thromboembolism should receive warfarin therapy for at least 3 months. At the present time, it is reasonable to treat the first recurrence with oral anticoagulants for 12 months and to indefinitely treat more than one recurrence. All patients at moderate to high risk for developing venous thromboembolism should receive prophylaxis. The approaches of proven value include low-dose heparin, LMWH, oral anticoagulants, and intermittent pneumatic compression.

Anticoagulants↗
PubMed1997

The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. The emerging theme of delayed recurrence.

BACKGROUND: Recent clinical trials of venous thromboembolism treatment suggest inadequate initial heparin therapy predisposes patients to late recurrence of thromboembolism. However, a recent review article was unable to demonstrate a relationship between initial heparin therapy and late recurrence. OBJECTIVE: To evaluate the relationship between initial heparin treatment and long-term clinical outcome in 3 consecutive, randomized, double-blind trials that used similar study designs and patient populations and objective documentation of recurrent venous thromboembolism. METHODS: The trials were performed sequentially and compared the use of continuous intravenous with subcutaneous heparin, continuous intravenous heparin for 10 or 5 days, and continuous intravenous heparin with once-daily subcutaneous low-molecular-weight heparin. All patients were followed up for 3 months to assess the a priori hypothesis that inadequate initial heparin therapy could lead to recurrent venous thromboembolism during long-term therapy with warfarin sodium. RESULTS: The following were the observed rates of recurrent venous thromboembolism: continuous intravenous heparin, 3 (5.2%) of 58 patients vs subcutaneous heparin, 11 (19.3%) of 57 patients; continuous intravenous heparin for 10 days, 7 (7.0%) of 100 patients or for 5 days, 7 (7.1%) of 99 patients; and continuous intravenous heparin, 15 (6.9%) of 219 patients vs low-molecular-weight heparin, 6 (2.8%) of 213 patients. Pooled analysis of the patients treated with continuous intravenous heparin showed that of the total 32 patients with recurrent venous thromboembolism, in 6 patients thromboembolism occurred early (< 10 days) and 26 patients thromboembolism occurred late. Of these patients, the majority (20/32 [62.5%]) had therapeutic prothrombin time or international normalized ratio values before or at the time of the recurrent thromboembolic event. CONCLUSION: Our findings demonstrate that the initial heparin treatment affects the long-term outcome. This conclusion applies when these data are analyzed for each individual study by treatment group, observed difference in outcome, and pooled analysis.

Anticoagulants↗
PubMed1997

Treatment of proximal vein thrombosis with subcutaneous low-molecular-weight heparin vs intravenous heparin. An economic perspective.

BACKGROUND: Subcutaneous low-molecular-weight heparin is at least as effective and safe as classic intravenous heparin therapy for the treatment of proximal vein thrombosis. Anticoagulant monitoring is not required with low-molecular-weight heparin. OBJECTIVE: To perform an economic evaluation of these therapeutic approaches by comparing cost and effectiveness. PATIENTS AND METHODS: A randomized trial in 432 patients with proximal vein thrombosis that compared intravenous heparin and low-molecular-weight heparin with objective documentation of clinical outcomes provided the opportunity to perform an analysis of cost-effectiveness to rank these alternative therapies in terms of both their cost and effectiveness. The economic viewpoint of this analysis was that of a third-party payer (ie, a ministry of health in Canada or an insurance company in the United States). RESULTS: In the intravenous heparin-treated group, the cost incurred for 100 patients was $414,655 (Canadian dollars) or $375,836 (US dollars), with a frequency of objectively documented venous thromboembolism of 6.9%. In the low-molecular-weight heparin-treated group, the cost incurred for 100 patients was $399,403 (Canadian dollars) or $335,687 (US dollars), with a frequency of objectively documented venous thromboembolism of 2.8%, thus providing a cost saving of $15,252 (Canadian dollars) or $40,149 (US dollars). Multiple sensitivity analyses were performed, and these procedures did not alter the findings of the study. CONCLUSIONS: The findings indicate that low-molecular-weight heparin therapy is at least as effective and safe but less costly than intravenous heparin treatment. The potential for outpatient therapy in up to 37% of patients who are receiving low-molecular-weight heparin would substantially augment the cost saving.

Anticoagulants↗
PubMed1997

Subcutaneous low-molecular-weight heparin vs warfarin for prophylaxis of deep vein thrombosis after hip or knee implantation. An economic perspective.

BACKGROUND: Postoperative venous thrombosis and pulmonary embolism present a major clinical threat to patients undergoing total hip or knee arthroplasty. We performed an economic evaluation of warfarin sodium and subcutaneous low-molecular-weight heparin sodium prophylaxis comparing cost and effectiveness. METHODS: A consecutive series of 1436 patients who underwent hip or knee arthroplasty comparing these 2 regimens in a randomized trial with objective documentation of outcomes provided the opportunity to perform economic evaluations for Canada and the United States. RESULTS: Deep vein thrombosis was documented in 231 (37.4%) of 617 patients given warfarin and in 185 (31.4%) of 590 patients given low-molecular-weight heparin (P = .03). In Canada, warfarin and low-molecular-weight heparin (tinzaparin sodium) incurred costs per 100 patients of $11,598 and $9,197, respectively, providing a cost savings of $2,401 for the low-molecular-weight heparin group. The drug cost of low-molecular-weight heparin (tinzaparin) was $6 per day and for warfarin was $0.32 per day. Sensitivity analysis showed that low-molecular-weight heparin is more costly if drug costs are increased by 1.5-fold (ie, the cost of tinzaparin is increased from $6 per day to $8.82 per day or more). In the United States, the analysis was also not definitive; low-molecular-weight heparin was more costly than warfarin at drug costs of $15 and $2.01 per day, respectively. CONCLUSIONS: Our findings indicate that the decision to use low-molecular-weight heparin or warfarin prophylaxis in patients undergoing major joint replacement surgery is a finely tuned trade-off. Prophylaxis with low-molecular-weight heparin is equally or more effective than the more complex prophylaxis with warfarin. Major bleeding is uncommon but less frequent with warfarin use. The most significant parameters that influence the comparative cost-effectiveness are the cost of the drug, the cost of international normalized ratio monitoring, and the costs associated with major bleeding. The analysis also demonstrates that the results are health care system dependent (Canada vs US). In Canada, low-molecular-weight heparin (tinzaparin) is less costly because it avoids the need for international normalized ratio monitoring. In the United States, the drug cost for low-molecular-weight heparin will likely be the principal determinant of relative cost-effectiveness.

Adult↗
PubMed1997

Low-molecular-weight heparin therapy and mortality.

There is ample evidence from clinical trials to justify giving certain low-molecular-weight heparins (LMWHs) subcutaneously rather than administering continuous intravenous unfractionated heparin for the initial treatment of venous thromboembolic disease. The LMWHs given by subcutaneous injection have a predictable anticoagulant response and prolonged duration of action. They can, therefore, be administered once or twice daily to treat venous thrombosis. Furthermore, treatment with these agents does not require laboratory monitoring. Eliminating the need for intravenous therapy and for laboratory monitoring should allow patients to be discharged earlier, and eventually lead to the outpatient treatment of venous thromboembolism. Studies to date indicate that LMWH is safer and as effective as continuous intravenous heparin in the treatment of venous thrombosis. The decreased mortality rates seen in two clinical trials, particularly in patients with metastatic cancer, were an unexpected but intriguing finding. This requires further confirmation, in larger prospective randomized trials.

Heparin, Low-Molecular-Weight↗
PubMed1997

Low-molecular-weight heparin: prophylaxis and treatment of venous thromboembolism.

Intravenous heparin followed by warfarin has been the classical anticoagulant therapy of acute venous thromboembolism for the last 30 years. Furthermore, low-dose unfractionated heparin given two to three times daily has been the most popular form of prophylaxis for venous thrombosis. In recent years, a number of low-molecular-weight heparins have become available for clinical trials. These agents have many advantages over unfractionated heparin and are now being used widely internationally for the prevention and treatment of venous thromboembolism. Indeed, low-molecular-weight heparin will undoubtedly replace intravenous unfractionated heparin not only in the treatment of venous thromboembolism, but in other conditions where heparin therapy is indicated. Whether or not the low-molecular-weight heparins can decrease or eliminate some of the complications of unfractionated heparin will depend on the outcome of future clinical trials.

Fibrinolytic Agents↗