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A G Turpie

Publications and source records attributed to A G Turpie.

At least 19 recordsLinked to original sources
PubMed2001

Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery.

BACKGROUND: Despite thromboprophylaxis, major knee surgery carries a high risk of venous thromboembolism. Fondaparinux, the first of a new class of synthetic antithrombotic agents, may reduce this risk. METHODS: In a double-blind study, we randomly assigned 1049 consecutive patients undergoing elective major knee surgery to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily, with both treatments initiated postoperatively. The primary efficacy outcome was venous thromboembolism up to postoperative day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The primary safety outcome was major bleeding. RESULTS: The primary efficacy outcome was assessed in 724 patients. The fondaparinux group had a significantly lower incidence of venous thromboembolism by day 11 (12.5 percent [45 of 361 patients]) than the enoxaparin group (27.8 percent [101 of 363 patients]; reduction in risk, 55.2 percent; 95 percent confidence interval, 36.2 to 70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the fondaparinux group (P=0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ. CONCLUSIONS: In patients undergoing elective major knee surgery, postoperative treatment with 2.5 mg of fondaparinux once daily was significantly more effective in preventing deep-vein thrombosis than 30 mg of enoxaparin twice daily.

Aged↗
PubMed2001

Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery.

BACKGROUND: Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk. METHODS: In a double-blind study, were randomly assigned 1711 consecutive patients undergoing surgery for fracture of the upper third of the femur to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily, initiated postoperatively, or 40 mg of enoxaparin once daily, initiated preoperatively, for at least five days. The primary efficacy outcome was venous thromboembolism up to postoperative day 11. Venous thromboembolism was defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were major bleeding and mortality from all causes. The duration of follow-up was six weeks. RESULTS: The incidence of venous thromboembolism by day 11 was 8.3 percent (52 of 626 patients) in the fondaparinux group and 19.1 percent (119 of 624 patients) in the enoxaparin group (P<0.001). The reduction in risk with fondaparinux was 56.4 percent (95 percent confidence interval, 39.0 to 70.3 percent). There were no significant differences between the two groups in the incidence of death or clinically relevant bleeding. CONCLUSIONS: In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism and equally safe.

Aged↗
PubMed2001

Setting a standard for venous thromboembolism prophylaxis.

Trials of the new antithrombotic agent fondaparinux sodium in patients undergoing orthopedic surgery are discussed. Phase II studies conducted in more than 900 hip-replacement and 400 knee-replacement patients demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism. Phase III trials evaluated the efficacy and safety of fondaparinux sodium 2.5 mg s.c. once daily starting six hours after surgery compared with enoxaparin for prevention of venous thromboembolism (VTE). Four multicenter, randomized, comparative, double-blind Phase III trials were conducted: two in total hip replacement patients (Ephesus and Pentathlon 2000), one in knee surgery patients (PentaMaks), and one in hip fracture surgery patients (Penthifra). All four studies followed the same design template, and the comparator was one of two regimens of enoxaparin approved for this indication. Enoxaparin sodium 30 mg s.c. every 12 hours starting postoperatively was used in Pentathlon 2000 and PentaMaks, and enoxaparin sodium 40 mg s.c. once daily starting preoperatively was used in Ephesus and Penthifra. The primary efficacy endpoint was the occurrence of VTE up to day 11, as determined by venography or confirmation of symptoms. The main safety outcome was occurrence of major bleeding. In total, 7344 patients were randomized and efficacy was evaluated in 5385 (73.3%). Risk of VTE was reduced by 50% in patients receiving fondaparinux compared with those receiving enoxaparin. Safety profiles for clinically relevant bleeding were similar between the two drugs. Fondaparinux sodium, a novel antithrombotic agent, is effective for the prevention of VTE, with a favorable safety profile, in patients undergoing major orthopedic surgery.

Anticoagulants↗
PubMed2001

Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial.

BACKGROUND: Low-molecular-weight heparins and heparinoids are superior to unfractionated heparin in the prevention and treatment of venous thromboembolism, but their safety and efficacy in acute ischaemic stroke are inadequately defined. METHODS: This randomised, double-blind, aspirin-controlled trial tested the safety and efficacy of treatment with high-dose tinzaparin (175 anti-Xa IU/kg daily; 487 patients), medium-dose tinzaparin (100 anti-Xa IU/kg daily; 508 patients), or aspirin (300 mg daily; 491 patients) started within 48 h of acute ischaemic stroke and given for up to 10 days. Primary intracerebral haemorrhage was excluded by computed tomography. Outcome was assessed, with treatment allocation concealed, by the modified Rankin scale at 6 months (independence [scores 0-2] vs dependence or death [scores 3-6]). FINDINGS: Of 1486 randomised patients, two did not receive treatment and 46 were lost to follow-up. The proportions independent at 6 months were similar in the groups assigned high-dose tinzaparin (194/468 [41.5%]), medium-dose tinzaparin (206/486 [42.4%]), or aspirin (205/482 [42.5%]). There was no difference in effect in any predefined subgroup, including patients with presumed cardioembolic stroke. Other outcome measures were similar between the treatment groups (disability, case-fatality, and neurological deterioration rates). During the in-hospital treatment period no patient assigned high-dose tinzaparin developed a symptomatic deep-vein thrombosis compared with nine assigned aspirin. Conversely, seven patients assigned high-dose tinzaparin developed symptomatic intracerebral haemorrhage compared with one in the aspirin group. INTERPRETATION: Treatment with tinzaparin, at high or medium dose, within 48 h of acute ischaemic stroke did not improve functional outcome compared with aspirin. Although high-dose tinzaparin was superior in preventing deep-vein thrombosis, it was associated with a higher rate of symptomatic intracranial haemorrhage.

Aged↗
PubMed2001

Comparison of a daily fixed 2.5-mg warfarin dose with a 5-mg, international normalized ratio adjusted, warfarin dose initially following heart valve replacement.

Patients starting oral anticoagulant therapy after heart valve replacement initially require a lower target international normalized ratio (INR) (2.0, range 1.5 to 2.6) because of a higher risk of bleeding until pericardial wires are removed. In a previous retrospective analysis, we observed a higher sensitivity to warfarin in these patients compared with nonsurgical patients. In a randomized clinical trial, we compared a fixed, lower dose of warfarin (2.5 mg) with the standard treatment consisting of a 5-mg loading dose, then adjusted to the target INR during the first 5 days of anticoagulation. INRs were measured daily, but the fixed dose was only modified on day 3 if the INR was <1.5 or >3.0. One hundred ninety-seven patients were considered eligible for the study. The 2 groups were well matched according to age, gender, body mass index, concomitant treatments, and type of valves implanted. The proportion of INRs >2.6 during the study period was 42.5% in the 5-mg group and 26.2% in the 2.5-mg group (p <0.05), and the proportion of INRs >3.0 on day 3 was 23.9% and 9.5% (p <0.05), respectively. In the 2.5-mg group, 35.7% of patients had an INR <1.5 on day 3 and had the dose increased (vs 3.5%, p <0.001); however, in the 5-mg group, 95.6% had the initial dose reduced, 49.6% had the dose withheld for at least 1 day, and the mean dose during the 5 days of study was 3.08 mg. Average time to achieve therapeutic range was higher in the 2.5-mg group (2.72 vs 1.98 days, p <0.0001), but the approach to the targeted INR was more regular, and the gap between target and mean INR on day 5 was smaller. There were no bleeding or thromboembolic complications in either group. Thus, a lower loading dose of warfarin in patients after heart valve replacement reduces excessive anticoagulation and offers a more regular achievement of the therapeutic target by reducing the number of dose adjustments. Daily monitoring of the INR is still recommended.

Aged↗
PubMed2001

Low-molecular-weight heparins in the treatment of acute coronary syndromes.

Platelet aggregation and activation of coagulation are key events in the development of acute coronary syndromes. Patients with an acute coronary syndrome are at high risk of death or myocardial infarction, and hence there is a strong rationale for the use of antithrombotic agents. Heparin has been shown to reduce the risk of death or myocardial infarction in aspirin-treated patients with acute coronary syndromes, but it has a number of limitations, including the need for regular monitoring and the risk of hemorrhage and thrombocytopenia. Low-molecular-weight heparins offer a number of practical and clinical advantages over unfractionated heparin, such as higher bioavailability and administration by subcutaneous injection. Several low-molecular-weight heparins are available that differ in their biochemical and pharmacologic properties, and it is not possible to predict their clinical efficacy from their pharmacologic profile. The decision regarding the use of a specific low-molecular-weight heparin should be based on the efficacy and safety data available for each product. In clinical trials comparing low-molecular-weight heparin with heparin, only enoxaparin sodium has been shown to reduce the risk of coronary events in patients with non-ST segment elevation acute coronary ischemia.

Acute Disease↗
PubMed2001

A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement.

BACKGROUND: Venous thromboembolism is a frequent complication of total hip replacement. The pentasaccharide Org31540/SR90107A, a highly selective, indirect inhibitor of activated factor X, is the first of a new class of synthetic antithrombotic agents. To determine the optimal dose for phase 3 studies, we conducted a dose-ranging study in which Org31540/SR90107A was compared with a low-molecular-weight heparin, enoxaparin, in patients undergoing total hip replacement. METHODS: In a double-blind study, patients were randomly assigned to postoperative administration of one of five daily doses of Org31540/SR90107A, given once daily, or to 30 mg of enoxaparin, given every 12 hours. Treatment was continued for 10 days or until bilateral venography was performed after a minimum of 5 days. RESULTS: Of 933 patients treated, 593 were eligible for the efficacy analysis. With Org31540/SR90107A a dose effect was observed (P=0.002), with rates of venous thromboembolism of 11.8 percent, 6.7 percent, 1.7 percent, 4.4 percent, and 0 percent for the groups assigned to 0.75 mg, 1.5 mg, 3.0 mg, 6.0 mg, and 8.0 mg of the drug, respectively, as compared with a rate of 9.4 percent in the enoxaparin group. The reduction in the risk of venous thromboembolism was 82 percent for the 3.0-mg Org31540/SR90107A group (P=0.01) and 29 percent for the 1.5-mg group (P=0.51). Enrollment in the 6.0-mg and 8.0-mg Org31540/SR90107A groups was discontinued because of bleeding complications. Major bleeding occurred 3.5 percent less frequently in the 0.75-mg group (P=0.01) and 3.0 percent less frequently in the 1.5-mg group (P=0.05) than in the enoxaparin group (in which the rate was similar to that in the 3.0-mg group). CONCLUSIONS: A synthetic pentasaccharide, Org31540/SR90107A, has the potential to improve significantly the risk-benefit ratio for the prevention of venous thromboembolism, as compared with low-molecular-weight heparin.

Adolescent↗
PubMed2001

Looking forward in the treatment of deep-vein thrombosis.

Clinical guidelines developed by the American College of Chest Physicians (ACCP) for the management of venous thromboembolism (VTE) are based on current evidence from randomized clinical trials and amended in response to emerging results. The standard treatment for VTE comprises in-hospital treatment with dose-adjusted unfractionated heparin (UFH) for a minimum of 5 days and oral anticoagulants for at least 3 months. Recent clinical studies show that subcutaneous low-molecular-weight heparins (LMWHs) in fixed doses according to body weight are as effective and safe as intravenous UFH in the initial treatment of deep-vein thrombosis, with or without pulmonary embolism. There is also evidence that the optimal duration of secondary thromboprophylaxis depends on assessable thromboembolic risk factors. The 1998 ACCP guidelines take account of this new evidence by advocating LMWHs as an alternative to standard UFH for the initial treatment of VTE and risk stratification of patients to guide duration of secondary thromboprophylaxis. Outpatient treatment of VTE with LMWHs has been shown to be feasible and is increasingly used in clinical practice, offering substantial economic benefits. Certain LMWHs appear to be effective at a once-daily dose. Evidence is now emerging that may clarify the role of inferior vena cava filters and thrombolysis in VTE management. Future versions of the ACCP guidelines may be expected to reflect new data from ongoing trials.

Anticoagulants↗
PubMed2001

Pentasaccharide Org31540/SR90107A clinical trials update: lessons for practice.

BACKGROUND: Patients undergoing orthopedic surgery are at particularly high risk for venous thromboembolism (VTE) and as such often receive prophylactic low-molecular-weight heparin (LMWH) or warfarin. However, efficacy and safety limitations of these agents have prompted a search for alternative antithrombotic drugs. METHODS: A new pentasaccharide, Org31540/SR90107A, the first of a class of synthetic and highly selective Factor Xa inhibitors, was investigated in a phase II double-blind, dose-ranging study for the prevention of deep vein thrombosis in 933 patients undergoing elective total hip replacement. The assessor-blind, comparative control was the LMWH enoxaparin. Patients were randomly assigned to 1 of 5 Org31540/SR90107A treatment groups (0.75, 1.5, 3, 6, or 8 mg/d subcutaneously) or to 30 mg enoxaparin subcutaneously every 12 hours. Treatment was started after surgery and continued for 5 to 10 days. Principal outcomes, determined on the basis of standard criteria, included venographically detected deep vein thrombosis and major bleeding. The 6.0- and 8.0-mg groups were discontinued early, in accordance with a protocol-defined safety rule. RESULTS: This phase II study showed improved dose-related efficacy and safety for Org31540/SR90107A versus enoxaparin and led to selection of 2.5 mg once daily as the optimal Org31540/SR90107A dose for large phase III trials in the prevention of VTE after total hip replacement, total knee replacement, and surgery for fractured hip. These studies have now been completed. CONCLUSIONS: Org31540/SR90107A is a new synthetic antithrombotic agent that has demonstrated a significant efficacy and safety dose effect in VTE prophylaxis after orthopedic surgery.

Antithrombin III↗
PubMed2001

Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.

1. Permanent therapy with oral anticoagulants offers the most consistent protection in patients with mechanical heart valves. 2. Antiplatelet agents alone do not consistently protect patients with mechanical prosthetic heart valves, including patients in sinus rhythm with St. Jude Medical valves in the aortic position. 3. Levels of oral anticoagulants that prolong the INR to 2.0 to 3.0 appear satisfactory for patients with St. Jude Medical bileaflet and Medtronic-Hall tilting disk mechanical valves in the aortic position, provided they are in sinus rhythm and the left atrium is not enlarged. Presumably, this is also true for the CarboMedics bileaflet valve, based on the observation of no clinically important difference in the rate of systemic embolism with this valve and the St. Jude Medical bileaflet valve. 4. Levels of oral anticoagulants that prolong the INR to 2.5 to 3.5 are satisfactory for tilting disk valves and bileaflet prosthetic valves in the mitral position. 5. Experience in patients with caged ball valves who had prothrombin time ratios reported in terms of the INR is sparse, because few such valves have been inserted in recent years. The number of surviving patients with caged ball valves continues to decrease. It has been suggested that the most advantageous level of the INR in patients with caged ball or caged disk valves should be as high as 4.0 to 4.9. However, others have shown a high rate of major hemorrhage with an INR that is even somewhat lower, 3.0-4.5. The problem is self-limited, however, because few such valves are being inserted. 6. In patients with mechanical heart valves, aspirin, in addition to oral anticoagulants, has been shown to diminish the frequency of thromboemboli. The risk of bleeding is somewhat increased if the INR is 2.0 to 3.0 or 2.5 to 3.5. However, if the INR is 3.0 to 4.5, the risk of bleeding becomes excessive with aspirin. There are no investigations in which aspirin 80 mg/d in combination with oral anticoagulants was evaluated. 7. Data are insufficient to recommend dipyridamole over low doses of aspirin in combination with warfarin. Whether dipyridamole plus aspirin is more effective than aspirin alone when used with warfarin is undetermined. 8. Patients with bioprosthetic valves in the mitral position as well as patients with bioprosthetic valves in the aortic position may be at risk for thromboemboli during the first 3 months after operation. 9. Among patients with bioprosthetic valves in the mitral position, oral anticoagulants at an INR of 2.0 to 2.3 were as effective as an INR of 2.5 to 4.0 and were associated with fewer bleeding complications during the first 3 months after operation.10. Aspirin may reduce the long-term frequency of thromboembolism in patients with bioprosthetic valves.

Administration, Oral↗
PubMed2000

Thrombosis prophylaxis in the acutely ill medical patient: insights from the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial.

The clinical benefit and cost-effectiveness of routine thromboprophylaxis in surgical patients has been well documented, but use of this approach in general medical patients remains controversial. Following is an overview of major insights from the prophylaxis in Medical patients with Enoxaparin (MEDENOX) trial, which was undertaken to evaluate the efficacy of 2 dosage regimens of the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism in acutely ill medical patients. MEDENOX was a prospective, double-blind, randomized, placebo-controlled trial, which enrolled 1,102 hospitalized patients from 68 centers in 9 countries. Patients were randomly assigned to receive 40 mg of enoxaparin, 20 mg of enoxaparin, or placebo, given subcutaneously once a day for 6-14 days. The primary outcome was venous thromboembolism (deep-vein thrombosis or pulmonary embolism) between days 1 and 14. At the 40-mg dose, the risk of venous thromboembolism was significantly reduced in patients with heart failure, as well as in patients with other medical illnesses, including respiratory failure, infectious disease, or rheumatic disorders. The incidence of venous thromboembolism was 5.5% in the group that received 40 mg of enoxaparin as compared with 14.9% in the group that received placebo (p <0.001), a benefit that was maintained at 3-month follow-up. There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin (15%) and the placebo group. Adverse effects did not significantly differ between the placebo group and either enoxaparin group. This study clearly establishes an effective strategy for lowering the risk of venous thromboembolism in the acutely ill population and provides a framework for future trials in this area.

Aged↗
PubMed2000

Impact of enoxaparin low molecular weight heparin in patients with Q-wave myocardial infarction.

A subgroup meta-analysis from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) and the Thrombolysis in Myocardial Infarction (TIMI) 11B studies has shown that enoxaparin is superior to unfractionated heparin in reducing the composite end points of death, myocardial infarction, and emergency revascularization in patients with Q-wave myocardial infarction. The beneficial treatment effect was significant at 43 days.

Aged↗
PubMed2000

Can we differentiate the low-molecular-weight heparins?

The low-molecular-weight heparins (LMWHs) have a number of therapeutic advantages, relative to standard unfractionated heparin (UFH). They are readily bioavailable when injected subcutaneously and can be given in fixed doses, allowing for far simpler administration. Several LMWHs are now commercially available, each demonstrating different physical and chemical properties and different activities in animal models of anticoagulation or hemorrhage. In clinical comparisons with placebo in the treatment of unstable coronary artery disease (UCAD), the LMWHs dalteparin sodium and nadroparin calcium have demonstrated good anticoagulant efficacy. In comparisons with UFH, on the other hand, only enoxaparin has shown superior anticoagulant activity, as reported in the results of the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Thrombolysis In Myocardial Infarction (TIMI) 11B trials. However, close scrutiny of the methodology of the clinical trials in UCAD reveals considerable differences in study designs, dosage regimens, duration of administration of active treatments, and the timing and definition of endpoints. Therefore, it would not be scientifically sound to compare results with the different LMWHs based on the current available studies. It is also not possible to draw any conclusions with regard to the relative efficacy of the different LMWHs, since there are no properly-sized comparative data between dalteparin sodium, enoxaparin sodium, and nadroparin calcium.

Anticoagulants↗