Costs and clinical outcomes associated with low-molecular-weight heparin vs unfractionated heparin for perioperative bridging in patients receiving long-term oral anticoagulant therapy

STUDY OBJECTIVES: There have been no health-care cost evaluations comparing the use of low-molecular-weight heparin (LMWH) to unfractionated heparin (UH) as "bridge therapy" in the perioperative period in patients receiving long-term oral anticoagulant (OAC) therapy who need interruption of therapy to undergo an elective surgical procedure. We performed a retrospective analysis of the medical and administrative records of health plan members in a managed care organization who underwent bridge therapy perioperatively with either i.v. UH, administered in a hospital setting, or LMWH, administered primarily in the outpatient setting using disease management guidelines. DESIGN: A retrospective analysis of medical and administrative records of treated health plan members meeting inclusion/exclusion criteria during the two study periods (ie, from 1994 to 1996 and from 1998 to 2000). SETTING: Staff-model health maintenance organization serving New Mexico. PATIENTS: The UH group included persons receiving long-term warfarin therapy from 1994 to 1996 (26 patients), and the LMWH group included persons receiving long-term warfarin therapy from 1998 to 2000 (40 patients) with perioperative use of heparin (either UH or LMWH) as bridge therapy for an elective surgical procedure. INTERVENTIONS: Costs were calculated for the period from 10 days before the procedure through 30 days after the procedure. The rates of adverse events (ie, valvular or mural thrombus, intracranial event, transient ischemic attack, peripheral arterial event, venous thromboembolic event, major and minor bleeding, thrombocytopenia, and death) occurring 1 to 30 days postprocedure were determined. MEASUREMENTS AND RESULTS: The groups were similar in age, sex, Charlson score, indication for long-term warfarin therapy (ie, arterial/cardiac vs venous), mean international normalized ratio prior to procedure, procedure duration, use of intraprocedural anticoagulant agents or thrombolytic agents, and use of general anesthesia during the procedure (all p > 0.05). A total of 34.6% of UH patients and 40.0% of LMWH patients experienced one or more clinical adverse events within 30 days of the postoperative period, a difference that was not statistically significant (p = 0.67). The mean total health-care costs were 31,625 dollars in the UH group and 18,511 dollars in the LMWH group (p < 0.01). The mean inpatient costs were 28,515 dollars in the UH group and 14,330 dollars in the LMWH group (p < 0.01). Outpatient surgery costs (1,159 dollars vs 53 dollars, respectively; p = 0.01) and pharmacy costs (639 dollars vs 133 dollars, respectively; p < 0.01) were higher in the LMWH group. CONCLUSIONS: The mean total health-care costs in the perioperative period were significantly lower (by 13,114 dollars) in patients receiving long-term OAC therapy using LMWH compared to those receiving it using UH for an elective surgical procedure. The cost savings associated with LMWH use were accomplished through the avoidance or minimization of inpatient stays and no increase in the overall rate of clinical adverse events in the postoperative period.     

Suppression of intimal hyperplasia with low molecular weight heparin in a sheep model.

BACKGROUND: Both unfractionated heparin (UH) and low molecular weight heparin (LMWH) in therapeutic anticoagulant doses have been shown to inhibit the development of intimal hyperplasia (IH) but with an increased risk of haemorrhage. In this study we investigated the effect of a "low dose" and "high dose" of UH and LMWH on the inhibition of IH together with their effect on plasma anti-Xa activity (AXa) and activated partial thromboplastin time (APTT) using a carotid artery sheep model. METHODS: A gelatin sealed Dacron patch graft was implanted into the common carotid artery of sheep which were randomly allocated to a control group (Group 1, n=10) or to one of four treatment groups receiving either low-dose LMWH enoxaparin 1 mg/kg/day (group 2, n=11), high-dose LMWH enoxaparin 2 mg/kg/day (Group 3, n=13), low-dose UH 125 u/kg/day (Group 4, n=10) or high-dose UH 250 u/kg/day (Group 5, n=10). The LMWH was administered subcutaneously once daily for four weeks and the UH in two divided doses per day for four weeks. During the treatment period, AXa and APTT were assayed from blood collected prior to and at 1 and 2 h after heparin administration on day 3, 7, 14, 21 and 28. On day 28, all animals were sacrificed and grafts were collected for analysis after taking blood samples prior to, then at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h following the last injection. Measurements of intimal thickness were obtained under light microscopy from eight transverse sections of each grafted artery using an eyepiece graticule. RESULTS: IH measurements (Mean+/-SD) were: Group 1 (controls) 288+/-86 microm, Group 2 (low-dose LMWH) 222+/-50 mm (p<0.05 compared to Group 1), Group 3 (high-dose LMWH) 203+/-78 microm (p<0.01), Group 4 (low-dose UH) 275+/-61 microm, and Group 5 (high-dose UH) 206+/-71 microm (p<0.01). There was no significant difference between Groups 2, 3 and 5. Groups 2, 3 and 5 demonstrated significant AXa during the 28 days period of which Groups 2 and 5 showed a significant increase in AXa levels with time. In the 24 h study after the last dose of treatment both Groups 2 and 3 showed longer AXa than group 5 (12-24 h vs 8 h). When compared to the control group, significant elevation of APTT was demonstrated in Groups 3 and 5. Group 5 had significantly longer APTT than Group 3. In the 24 h study, APTT reflected the changes of AXa in all groups. CONCLUSIONS: In this study the LMWH enoxaparin was effective in reducing the formation of IH both at a standard anticoagulant therapeutic dose of 2 mg/kg/day and also at a lower dose of 1 mg/kg/day.     

Comparison of low-molecular-weight heparin, administered primarily at home, with unfractionated heparin, administered in hospital, and subcutaneous heparin, administered at home for deep-vein thrombosis.

In this study, 294 patients with acute proximal DVT (deep venous thrombosis) were randomly assigned to receive intravenous standard heparin in the hospital (98 patients) or low-molecular-weight heparin (LMWH) (nadroparin 0.1 mL [equivalent to 100 AXa IU] per kg of body weight subcutaneously twice daily) administered primarily at home (outpatients) or alternatively in hospital (97 patients) or subcutaneous calcium heparin (SCHep) (99 patients, 0.5 mL bid) administered directly at home. The study design allowed outpatients taking LMWH heparin to go home immediately and hospitalized patients taking LMWH to be discharged early. Patients treated with standard heparin or LMWH received the oral anticoagulant starting on the second day, and heparin was discontinued when the therapeutic range (INR 2-3) had been reached. Anticoagulant treatment was maintained for 3 months. Patients treated with SCHep were injected twice daily for 3 months without oral anticoagulants. Patients were evaluated for inclusion and follow-up with color duplex scanning. Venography was not used. In case of suspected pulmonary embolism (PE) a ventilatory-perfusional lung scan was performed. Endpoints of the study were recurrent or extension of DVT, bleeding, the number of days spent in hospital, and costs of treatments. Of the 325 patients included, 294 completed the study. Dropouts totaled 31 (10.5%); six of the 325 included patients (1.8%) died from the related, neoplastic illness. Recurrence or extension of DVT was observed in 6.1% of patients in the LMWH group, in 6.2% in the standard heparin group, and in 7.1% in the SCHep group. Most recurrences (11/17) were in the first month in all groups. Bleedings were all minor, mostly during hospital stay. Hospital stay in patients treated with LMWH was 1.2+/-1.4 days in comparison with 5.4+/-1.2 in those treated with standard heparin. There was no hospital stay in the SCHep group. Average treatment costs in 3 months in the standard heparin group (US $2,760) were considered to be 100%; in comparison costs in the LMWH group was 28% of the standard heparin and 8% in the SCHep group. This study indicated that LMWH and SCHep can be used safely and effectively to treat patients with proximal DVT at home at a lower cost.     

Cost-effectiveness of low-molecular-weight heparin in the treatment of proximal deep vein thrombosis

OBJECTIVE: To estimate the cost-effectiveness of low-molecular-weight heparin (LMWH) in the treatment of proximal lower extremity deep venous thrombosis. DESIGN: Cost-effectiveness analysis that includes the treatment of the index case and simulated 3-month follow-up. SETTING: Acute care facility. PATIENTS AND PARTICIPANTS: Hypothetical cohorts of 1,000 patients who present with proximal deep venous thrombosis. INTERVENTIONS: Intravenous unfractionated heparin (UH), LMWH (40% at home, 60% in hospital), or selective UH/LMWH (UH for hospitalized patients and LMWH for patients treated at home). MEASUREMENTS AND MAIN RESULTS: The outcomes were recurrent thrombosis, mortality, direct medical costs, and marginal cost-effectiveness ratios from the payer’s perspective. At the base-case and under most assumptions in the sensitivity analysis, the LMWH and the selective UH/LMWH strategies dominate the UH strategy i.e., they result in fewer cases of recurrent thrombosis and fewer deaths, and they save resources. The savings occur primarily by decreasing the length of stay. The LMWH strategy resulted in lower costs as compared with the UH strategy when the proportion of patients treated at home was more than 14%. Treating 1,000 patients with the LMWH strategy as compared with the UH/LMWH strategy would result in 10 fewer cases of recurrent thrombosis, 1.2 fewer deaths, at an additional cost of $96,822; the cost-effectiveness ratio was $9,667 and $80,685 per recurrent thrombosis or death prevented, respectively. CONCLUSIONS: Treatment with LMWH leads to savings and better outcomes as compared with UH in patients with lower extremity deep venous thrombosis. The selective UH/LMWH strategy is an alternative option. Presented in part at the 20th annual meeting, Society of General Internal Medicine, Washington, DC, May 1–3, 1997.     

No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis

BACKGROUND: Low-molecular-weight heparin (LMWH) is a popular alternative to unfractionated heparin (UH) for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), in part based on the perception of a lower risk for heparin-induced thrombocytopenia (HIT). To investigate the evidence supporting this perception, we performed a metaanalysis to compare the incidence of thrombocytopenia between LMWH and UH during PE and/or DVT treatment. METHODS: Randomized trials comparing LMWH with UH for PE and/or DVT treatment were searched for in the MEDLINE database, bibliographies, and by correspondence with published investigators. Two reviewers independently selected high-quality studies and extracted data regarding heparin-associated thrombocytopenia (HAT), HIT confirmed by laboratory testing, and heparin-induced thrombocytopenia with thrombosis (HITT). Outcome rates between LMWH and UH were compared using a binomial, generalized linear mixed model with a logit link and Gaussian random effects for study. RESULTS: Thirteen studies involving 5,275 patients met inclusion criteria. There were no statistically significant differences in HAT rates between the two treatments (LMWH, 1.2%; UH, 1.5%; p = 0.246). The incidence of documented HIT and HITT was too low to make an adequate comparison between groups. CONCLUSIONS: Our review disclosed no statistically significant difference in HAT between LMWH and UH and insufficient evidence to conclude that HIT and HITT rates were different between them. There was no evidence from randomized comparative trials to support the contention that patients receiving treatment for PE or DVT with UH are more prone to these complications than those receiving LMWH.     

Cost comparison of at-home treatment of deep venous thrombosis with low molecular weight heparin to inpatient treatment with unfractionated heparin

Abstract
Aims : Low molecular weight heparins (LMWH) permit safe and effective treatment of uncomplicated deep venous thrombosis (DVT) at home. The aim of this study was to evaluate the cost minimization, cost shifting and patient satisfaction associated with at-home DVT treatment using the LMWH enoxaparin, compared to standard inpatient care in an Australian health-care setting.
Methods : Subjects presenting with a principal diagnosis of uncomplicated DVT to the Emergency Department at The Queen Elizabeth Hospital, Adelaide, were recruited over 1997–1999. Costs to the hospital, to Federal funding (Medicare) and to patients were tracked prospectively, and satisfaction was also measured. Subjects were matched to historical controls (1994–1997) for age, gender and level of comorbidity (same or lower) by two medical officers who were blinded to costs. Control costs were obtained using the clinical costing system Trendstar®, and adjusted for consumer price index.
Results : Twenty-eight subjects participated in the at-home programme. Of these, 26 were discharged without any inpatient admission (including one who agreed to self-injection) and two were admitted briefly. Audit demonstrated that only 29% of eligible subjects were managed at home. Mean (SEM) total treatment cost was $756 (76) per patient for at-home, and $2208 (146) for controls. Minimal cost shifts to patients and to Medicare occurred, and satisfaction was high.
Conclusions : At-home treatment of uncomplicated DVT using enoxaparin in an Australian metropolitan setting provides effective cost minimization, with little cost-shifting. Our cost minimisation estimates are conservative as most at-home subjects received enoxaparin twice daily (now used once per day) and controls had at least as high comorbidity. However, uptake of the at-home programme was limited. (Intern Med J 2002; 32: 29–34)     

The home treatment of deep vein thrombosis with low molecular weight heparin, forced mobilisation and compression.

BACKGROUND: The aim of this prospective study was to analyse a group of patients with DVT (deep vein thrombosis) treated at home with LMWH (low-molecular weight heparin), compression and intensive mobilisation and to evaluate its feasibility, efficacy and safety from possible risks of pulmonary embolism. METHODS: From March 1997 to September 1999, 96 consecutive patients with diagnosed DVT were enrolled in a prospective study and treated at home with enoxaparin (Clexane Rh ne-Poulenc) administered subcutaneously at doses depending on body weight (1 mg/kg) b.i.d. for a minimum of seven days. Oral anticoagulants were started two days before discontinuing LMWH and given later for three months according to the haemocoagulation parameters. All patients wore elastic second degree compression stockings during the whole period of treatment and for 12 months there after. They were encouraged to walk 1-3 km daily. The sites of thrombosis were ilio-femoral vein--38 patients (40%), femoral or popliteal vein--32 patients (33%), crural veins--26 patients (27%). According to our surgical criteria two years ago 17 patients would have been operated on and trombectomy performed. The diagnosis was made by compression ultrasonography using a colour duplex scanner (Acuscan 125), by contrast phlebography, and platelet scintigraphy (Tromboscint test). Perfusion-ventilation scintigraphy of the lungs was performed only if there were clinical signs or even a suspicion of pulmonary embolism and on all patients with iliofemoral thrombosis. Perfusion gamagraphy of lungs was carried out on 51 patients where thrombosis was localised in proximal veins. RESULTS: In 27 patients there were signs of non-fatal pulmonary embolism (53%), but only seven patients (26%) suffered mild non-specific clinical signs; 20 patients with diagnosed pulmonary embolism (74%) were symptom-free. Out of 96 patients, three admitted to hospital (3%), 67 (70%) injected LMVH themselves and felt comfortable. Eight to 12 weeks after this treatment control sonography and phlebography were carried out in 70 patients to assess the localisation and progress of the thrombosis. In 51% (36 patients) partial and 31% (22 patients) total recanalisation was found. Five out of 96 complained of minor bleeding (5%). No thrombocytopenia was noticed. The first five days on home treatment were crucial. All patients were able to walk and live at home without difficulty. None of our patients with proximal deep vein thrombosis used a vena cava filter. CONCLUSIONS: Home treatment of DVT is possible and is effective, safe and less costly on average and per patient 40% in costs was saved compared with those of a hospital stay in spite of the greater expense of LMWH. The patients who received LMWH spent a mean of 1.2 days in the hospital, as compared with 12.7 days for the standard-heparin group.     

Low-molecular-weight heparin versus unfractionated heparin in the treatment of patients with acute pulmonary thromboembolism

BACKGROUND: Low-molecular-weight heparin (LMWH) appears to be as effective as unfractionated heparin (UFH) for both treatment and prophylaxis of deep vein thrombosis (DVT), but limited data are available for its use in acute pulmonary thromboembolism (PTE). OBJECTIVE: To determine whether enoxaparin, a LMWH, was clinically as efficient and safe as UFH in patients with a diagnosis of acute PTE. MATERIAL AND METHODS: After exclusion of those with massive forms, 59 patients with acute PTE were randomly assigned to either subcutaneous enoxaparin given twice daily (1 mg/kg/dose) or adjusted dose intravenous UFH. Oral anticoagulant treatment was begun on the second day and was given for at least 6 months. We compared the treatment regimens at day 8 and day 90 with respect to a combined end point of major bleeding, recurrent venous thromboembolism (VTE), and death. RESULTS: In the first 8 days of treatment, 1 of 30 patients assigned to receive UFH (3.3%) reached one of the end points (recurrence), as compared with none of 29 patients assigned to enoxaparin. Statistically this difference was not significant (p = 0.508). By day 90, 3 patients assigned to UFH (10%) had symptomatic recurrent VTE, as compared with 1 patient assigned to enoxaparin (3.4%). There was neither major bleeding nor death in the study groups. There was an absolute difference of 6.4 percentage points between the two treatment groups, but the difference was statistically not significant (p = 0.318). CONCLUSION: Initial subcutaneous treatment with enoxaparin appeared to be as effective and safe as UFH in acute PTE.     

Identifying inappropriate hospital stay in patients with venous thromboembolism

Background: Traditionally, venous thromboembolism has been treated in a hospital setting. Nowadays, low molecular weight heparin (LMWH) preparations allow most deep venous thrombosis (DVT) patients to benefit from home therapy. The objective of this study was to evaluate whether the previous treatment of deep venous thrombosis in a hospital setting was appropriate in the context of modern opinion, using the Dutch Appropriateness Evaluation Protocol (DAEP). If so, the DAEP could be used to assess the appropriateness of the present hospital stay of other patient groups. Methods: A retrospective study of patients treated from 1995 to 1998 for DVT or for pulmonary embolism (PE), before the implementation of ambulatory treatment, was conducted that assessed the appropriateness of the patient's hospital stay using the DAEP. Results: Only 27.1% of the treatments for DVT were found to be appropriate in a hospital setting and related to specific hospital care. Inappropriate stay was mostly related to delays in hospital and discharge procedures. Of the patients with PE, 50.2% needed a hospital stay. This proportion was statistically significantly higher than in DVT patients (p<0.001). The extent of the DVT was not related to the length of bed rest prescribed. Conclusions: The DAEP was able to identify inappropriate hospital stay in the past within the DVT patient group. Further exploration of the potential of the DAEP to identify patient groups who could be treated at home is warranted.     

Home treatment of deep venous thrombosis with low molecular weight heparin: Long-term incidence of recurrent venous thromboembolism

Outpatient treatment of deep venous thrombosis (DVT) with low molecular weight heparin (LMWH) seems as safe and effective as inpatient treatment with unfractionated heparin (UFH). However, most of the randomized trials comparing a LMWH with UFH described clinical outcomes within 3-6 months. The long-term incidence of recurrent VTE after treatment of DVT with LMWH remains to be established. The primary objective of this retrospective study was to document the long-term incidence of recurrent venous thromboembolism (VTE) in patients with DVT treated with a LMWH, nadroparin in an outpatient basis. The patients were evaluated 46 months after inclusion in two cohorts comparing home treatment with nadroparin (n = 130) with in-hospital treatment with intravenous UFH (n = 149). More than 60% of the patients in the nadroparin group could be treated at home, either entirely or after a short stay in hospital. The age-adjusted thrombosis-free survival was not statistically significant between nadroparin and UFH-treated patients (P = 0.084). There was a nonsignificant trend favoring nadroparin as compared with UFH. The hazard ratio (HR) for recurrent VTE in the nadroparin group with respect to the UFH group was 0.44 (95% confidence interval, 0.17-1.12). No significant differences were observed in overall mortality or major hemorrhage between the two treatment groups. Our study suggests that home treatment of DVT with LMWH is at least as effective and safe as in-hospital UFH after a long-term follow-up period.     

Reduction in thrombus extension and clinical end points in patients after initial treatment for deep vein thrombosis with the fixed-dose body weight-independent low molecular weight heparin certoparin.

Low molecular weight heparin (LMWH) is effective in the treatment of acute deep vein thrombosis (DVT) in adults. This has not been demonstrated for one LMWH alone. The relationship between venographic changes due to LMWH therapy and clinical outcome in the initial treatment period has not been reported. A pooled analysis of two clinical trials was performed. The trials compared a fixed-dose, body weight-independent, subcutaneous LMWH, certoparin (8000 antifactor Xa [aXa] U twice a day [b.i.d.]), with an adjusted-dose intravenous unfractionated heparin (UFH) with respect to venographic changes expressed as Marder score and occurrence of recurrent venous thromboembolism, major bleeding, and mortality. The Marder score was 23.2 +/- 8.4 in patients randomized to LMWH (n = 299 paired phlebograms) and 23.9 +/- 8.9 in patients allocated to UFH (n = 297 paired phlebograms) at entry (2p = 0.23) and 18.9 +/- 9.7 and 20.5 +/- 9.9 at the end of the initial therapy (2p = 0.04), respectively. The composite outcome of recurrent venous thromboembolism, major bleeding, and mortality occurred less frequently during treatment with LMWH (n = 393) than it did with UFH (n = 404, 1.3% versus 5.0%, risk reduction [RR] 0.26, 95% confidence interval [CI] 0.11 to 0.63, 2p = 0.004). Single events of recurrent thromboembolism (2p = 0.12), major bleeding (2p = 0.03), and mortality (2p = 0.12) were observed less frequently with LMWH. A trend toward a lack of regression of thrombus size was observed in recurrent venous thromboembolism (2p = 0.08). Body weight-independent LMWH significantly reduces thrombus size and the incidence of composite outcome during the initial treatment of acute proximal venous thrombosis compared with adjusted dose intravenous UFH. The data indicate a relation between an unimproved Marder score and a recurrent venous thromboembolism.     

Non-ST elevation acute coronary syndrome: changes of parameters of hemostasis during and after treatment with unfractionated heparin and enoxaparin

AIM: To compare changes of parameters of hemostasis in patients with non-ST elevation acute coronary syndrome (NSTEACS) during and after treatment with unfractionated heparin (UFH) and low molecular weight heparin (LMWH) enoxaparin. MATERIAL: Control groups of 2 randomized studies of effects of thienopyridines in NSTEACS with similar inclusion criteria. METHODS: In patients (n=18) of study one UFH was infused intravenously for 54.2+/-22.3 h, in patients of study two subcutaneous enoxaparin 1 mg/kg b.i.d. was used for 76.2+/-28.3 h. Levels of D-dimer (DD), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), von Willebrand factor (vWF), fibrinogen, tissue plasminogen activator (TPA) and activity of its inhibitor (PAI), soon after start of treatment with heparins and in 1, 3, 7 and 14 days. RESULTS AND CONCLUSION: Short term lowering of DD and TAT levels occurred during UFH infusion apparently reflecting primary antithrombin action of UFH. During LMWH use DD level remained unchanged however its lowering was observed after cessation of LMWH (on days 7 and 14). The use of LMWH was not associated with increases of thrombinemia (TAT), thrombin generation (F1+2), and fibrinogen which were registered after end of UFH infusion (days 3, 7 and 14). Neither UFH nor LMWH prevented acute phase vWF elevation. The use of both heparins was associated with changes that could be interpreted as profibrinolytic. In LMWH treated patients these changes (elevations of TPA level) became manifested early (on day 3) and were short lived while in UFH treated patients they appeared later (on day 7) and were prolonged (as lowered PAI activity on day 14).     

Identifying orthopedic patients at high risk for venous thromboembolism despite thromboprophylaxis

OBJECTIVE: To evaluate risk factors for venous thromboembolism (VTE) despite thromboprophylaxis in major orthopedic surgery patients at a tertiary care hospital. METHODS: Charts from consecutive patients who underwent total hip replacement (THR), total knee replacement (TKR), or hip fracture surgery (HFS) [hip pinning or hemiarthroplasty] from August 1, 1999, to April 30, 2000, at a large Canadian teaching hospital were abstracted using standardized case report forms. Data were collected on patient characteristics, surgical characteristics, and thromboprophylaxis regimen. Results of tests performed for suspected VTE were documented. Associations between characteristics of interest and objectively confirmed VTE were examined in multivariate analysis. RESULTS: Over the study period, 310 patients underwent major orthopedic surgery and received standard thromboprophylaxis with either dalteparin or enoxaparin (mean duration of prophylaxis, 7 days). Of these, 34% underwent THR, 30% underwent TKR, and 36% underwent HFS. Of 83 suspected cases of VTE, 44 cases (7 proximal and 37 distal deep venous thrombosis [DVT]); 14% of study population) were confirmed with objective testing. Multivariate analyses revealed that knee surgery (odds ratio [OR], 4.8; 95% confidence interval [CI], 2.3 to 10.1) and type of low molecular weight heparin (LMWH) [enoxaparin (more protective): OR, 0.39; 95% CI, 0.20 to 0.80] independently predicted VTE. No patient characteristics (including previous VTE, malignancy, hormonal therapy, postoperative complications) were associated with VTE. CONCLUSION: Despite standard thromboprophylaxis, symptomatic breakthrough VTE, primarily distal DVT, developed in 14% of patients undergoing major orthopedic surgery. Factors that independently predicted VTE in our population were TKR surgery and type of LMWH. TKR patients may warrant more aggressive postoperative physiotherapy and ambulation and adjunctive prophylactic measures such as pneumatic compression. Due to the heterogeneity of different LMWH compounds, direct comparison of the effectiveness of enoxaparin with dalteparin for orthopedic prophylaxis in prospective, randomized trials seems warranted.     

Cost implications of testing strategy in patients with syncope: randomized assessment of syncope trial

OBJECTIVES: We sought to assess the cost implications of two investigation strategies in patients with unexplained syncope. BACKGROUND: Establishing a diagnosis in patients with unexplained syncope is complicated by infrequent and unpredictable events. The cost-effectiveness of immediate, prolonged monitoring as an alternative to conventional diagnostic strategies has not been studied. METHODS: Sixty patients (age 66 +/- 14 years; 33 males) with unexplained syncope and LV ejection fraction >35% were randomized to conventional testing with an external loop recorder, tilt and electrophysiologic (EP) testing, or prolonged monitoring with an implantable loop recorder with one-year monitoring. If patients remained undiagnosed after their assigned strategy, they were offered a crossover to the alternate strategy. Cost analysis of the two testing strategies was performed. RESULTS: Fourteen of 30 patients who were being monitored were diagnosed at a cost of 2,731 Canadian dollars +/- 285 Canadian dollars per patient and 5,852 Canadian dollars +/- 610 Canadian dollars per diagnosis. In contrast, only six of 30 conventional patients were diagnosed (20% vs. 47%, p = 0.029), at a cost of 1,683 Canadian dollars +/- 505 Canadian dollars per patient (p < 0.0001) and 8,414 Canadian dollars +/- 2,527 Canadian dollars per diagnosis (p < 0.0001). After crossover, a diagnosis was obtained in 1 of 5 patients undergoing conventional testing, compared with 8 of 21 patients who completed monitoring (20% vs. 38%, p = 0.44). Overall, a strategy of monitoring followed by tilt and EP testing was associated with a diagnostic yield of 50%, at a cost of 2,937 Canadian dollars +/- 579 Canadian dollars per patient and 5,875 Canadian dollars +/- 1,159 Canadian dollars per diagnosis. Conventional testing followed by monitoring was associated with a diagnostic yield of 47%, at a greater cost of 3,683 Canadian dollars +/- 1,490 Canadian dollars per patient (p = 0.013) and a greater cost per diagnosis (7,891 Canadian dollars +/- 3,193 Canadian dollars, p = 0.002). CONCLUSIONS: A strategy of primary monitoring is more cost-effective than conventional testing in establishing a diagnosis in recurrent unexplained syncope.     

Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis.

BACKGROUND: The safety and efficacy of taking low-molecular-weight heparin at home was previously demonstrated in a clinical trial in which patients with acute proximal deep vein thrombosis were randomized to receive either intravenous standard heparin in the hospital or subcutaneous low-molecular-weight heparin administered primarily at home. Treatment in the home has the potential to substantially reduce the cost to the health care system. METHODS: To conduct an economic evaluation we prospectively collected data on resource use and health-related quality of life (Medical Outcomes Study Short-Form 36) on the 300 patients who formed the trial stratum presenting with proximal vein thrombosis as outpatients, of whom 151 received standard heparin and 149 received low-molecular-weight heparin. The primary viewpoint of the analysis was societal, and costs included health care costs, patient travel costs, and productivity costs as a result of time off work. Costs were assessed over a period of 3 months from randomization. Quality of life was assessed as the change in Short-Form 36 domain scores from baseline to day 7 for each treatment group. All costs are reported in 1997 Canadian dollars. RESULTS: There were 11 recurrent thromboembolic events and 1 bleed in the 151 patients who received standard heparin; the corresponding data for the 149 patients receiving low-molecular-weight heparin were 10 and 4, respectively. The mean cost per patient who received standard heparin was Can $5323 compared with Can $2278 for low-molecular-weight heparin, a total societal cost savings per patient using low-molecular-weight heparin of Can $3045 (95% confidence interval, Can $2012-$4050). There was no difference in quality of life between the 2 groups except for the domain of social functioning, where a greater improvement from baseline to day 7 was observed for the low-molecular-weight heparin group vs the standard heparin group (P =.005). CONCLUSIONS: For patients with acute proximal deep vein thrombosis, treatment at home with low-molecular-weight heparin is less costly than hospital-based treatment with standard heparin. The economic evidence in favor of outpatient treatment with low-molecular-weight heparin exhibits dominance; a situation of reduced cost is created with no compromise in clinical outcomes or patients' quality of life.     

Periprocedural bridging therapy with low-molecular-weight heparin in chronically anticoagulated patients with prosthetic mechanical heart valves: experience in 116 patients from the prospective BRAVE registry

BACKGROUND AND AIM of the study: The study aim was to determine the safety and feasibility of a standardized bridging regimen in patients with mechanical heart valves at high thromboembolic risk, using low-molecular-weight heparin (LMWH). METHODS: Since the year 2000, all patients at the authors' institution, with mechanical heart valves and a need for periprocedural interruption of oral anticoagulation (OAC), were prospectively enrolled in this registry. Patients were treated with enoxaparin following a pre-specified, standardized bridging regimen. The main outcome measures were the incidence of hemorrhagic or thromboembolic events. The follow up period was 30 days after hospital discharge. RESULTS: A total of 116 patients was included (31 with mitral valve replacement, 76 aortic valve replacement, nine double valve replacement). Patients underwent either major surgery (n = 25), minor surgery (n = 36), pacemaker implantation (n = 21), or coronary catheterization (n = 34). Bridging therapy with enoxaparin was administered for a mean of 7.0 +/- 4.6 days. Eighteen patients (15.5%) were treated as outpatients. In 35 patients (34%) with renal impairment (creatinine clearance <50 ml/min), LMWH dosage was halved. No thromboembolic (95% CI 0-3.1%) and only one major bleeding complication occurred (0.86%; 95% CI 0.02-4.7%); minor bleeding occurred in 10 patients (8.6%; 95% CI 4.2-15.3%). The hemorrhages arose after a mean of 5.4 +/- 1.4 days LMWH therapy. CONCLUSION: Bridging therapy following a standardized LMWH-based regimen with enoxaparin was effective and relatively safe in a large cohort of patients with mechanical heart valves. Extended duration of LMWH therapy seems to promote the incidence of hemorrhage. Neither dose reduction in patients with renal impairment nor outpatient treatment affected the safety and efficacy of this bridging regimen. These findings warrant that more extensive studies be conducted to investigate the safety of this approach.     

Effects of enoxaparin and nadroparin on major cardiac events in high-risk unstable angina treated with a glycoprotein IIb/IIIa inhibitor

Clinical trials have reported the beneficial effects of platelet glycoprotein (GP) IIb/IIIa receptor antagonists and low-molecular-weight heparins (LMWH) on major cardiac events (MACE) in patients presenting with unstable angina or non-ST elevation myocardial infarction. A number of studies have documented the significant superiority of low-molecular-weight heparins, especially enoxaparin, over unfractionated heparin in the treatment of acute coronary syndromes. The purpose of this study was to compare the effects of two different LMWHs, enoxaparin and nadroparin, accompanied by platelet GP IIb/IIIa inhibition on MACE in high-risk unstable angina. The study was designed as an open-label and observational study. Sixty-eight patients presenting with unstable angina associated with high-risk criteria were randomly assigned to treatment with enoxaparin plus tirofiban (36 patients, mean age 57 +/- 11) or nadroparin plus tirofiban (32 patients, mean age: 58 +/- 8). In-hospital MACE including acute myocardial infarction (AMI), recurrent refractory angina, death, stroke, and urgent revascularization were compared between the study groups. Patient characteristics and durations of LMWH and tirofiban treatments were not different between the study groups. Coronary artery risk factors, except family history (which was observed more frequently in the enoxaparin group, P = 0.02), were also similar. MACE between the enoxaparin and nadroparin groups including AMI (5.5%, 6%), recurrent refractory angina (19%, 12%), death (0%, 3%), stroke (was not observed in either group), urgent revascularization (14%, 12%) and total MACE (19%, 15%) were not different. Enoxaparin and nadroparin, accompanied by GP IIb/IIIa inhibitor therapy, have similar effects on the development of major cardiac events in patients presenting with unstable angina and high-risk characteristics.     

Extended enoxaparin monotherapy for acute symptomatic pulmonary embolism

We investigated the efficacy and safety of extended enoxaparin monotherapy in symptomatic patients with acute pulmonary embolism (PE). We randomized 40 patients in a 1:1 allocation to enoxaparin monotherapy (1 mg/kg twice daily for 10-18 days, and then 1.5mg/kg once daily until day 90) (n = 20) or to enoxaparin 1.0 mg/kg twice daily as a bridge to warfarin with a target international normalized ratio of 2.0-3.0 for 90 days (at least 10 doses of enoxaparin overlapping with warfarin for at least 4 days) (n = 20). All patients underwent echocardiography, cardiac troponin I (TnI), and brain natriuretic peptide testing to identify patients with an increased likelihood of adverse clinical outcomes. The end-points were newly diagnosed deep venous thrombosis (DVT) or PE and bleeding events through day 90. In 15 patients on extended enoxaparin therapy, we used repeated measure analysis of variance (ANOVA) to investigate differences in anti-Xa levels obtained at 2, 4, 8 and 12 weeks. The patients' mean age was 52 +/- 17 years; the most common comorbidities were obesity (58%), hypertension (30%), concomitant DVT (30%) and cancer (15%). Twelve (30%) patients had elevated cardiac Tnl >0.1 mg/l and 11 (28%) had moderate or severe right ventricular dysfunction on echocardiography. Ten (25%) patients received thrombolysis with a continuous infusion of 100 mg alteplase prior to randomization. During a 90-day follow-up, one patient from the enoxaparin monotherapy group suffered symptomatic distal DVT; one from the warfarin group had recurrent symptomatic PE (p = 1.0). None of the study patients had major hemorrhage; two warfarin group patients had minor bleeding compared with none in the enoxaparin monotherapy group (p = 0.49). Repeated measure ANOVA did not reveal significant differences in anti-Xa levels over time (p = 0.217). In patients with acute symptomatic PE, extended enoxaparin monotherapy is feasible and warrants further investigation in a large clinical trial.     

Pre-operative plasma levels of soluble fibrin polymers correlate with the development of deep vein thrombosis after elective neurosurgery.

The role of blood tests in identifying patients at high risk for post-operative venous thromboembolism is undefined. The aim of this study was to evaluate the correlation between pre-operative plasma levels of soluble fibrin polymers (SFP), as determined by a recently developed enzyme-linked immunosorbent assay (ELISA) assay (TpP), and the incidence of deep vein thrombosis (DVT) after elective neurosurgery. Blood samples for SFP assay were withdrawn on the day before surgery from 157 consecutive patients undergoing elective neurosurgery for brain or spinal tumour. Patients were randomized to subcutaneous enoxaparin (40 mg once daily) or placebo given for at least 7 days. All patients wore compression stockings. DVT was assessed by bilateral venography, performed on day 8 +/- 1. Thirty-four patients (21.7%) were found to have a DVT, proximal in 11 (7%) and isolated distal in 23. Patients with and without DVT had a plasma pre-operative SFP levels of 6.2 +/- 4.6 and 1.9 +/- 1.5 mg/ml respectively (mean +/- SD) (P < 0.001). SFP levels in patients with proximal and isolated distal DVT were 7.6 +/- 5.1 and 5.5 +/- 4.4 microg/ml, respectively (P = 0.22). SFP cut-off levels categorized patients into three classes of DVT incidence. The incidence of DVT was 7.4% (6 of 81) for SFP levels < 2 microg/ml, 20.4% (11 of 54) for levels between 2 and 4.5 microg/ml, and 77.3% (17 of 22) for levels > 4.5 microg/ml (P= 0.001, Cochran-Mantel-Haenszel test). We conclude that pre-operative SFP levels correlate with post-operative DVT in elective neurosurgery patients. Further studies are required to define whether pre-operative SFP measurement could be useful in patient management.     

Low-molecular-weight heparin for the treatment of patients with mechanical heart valves

BACKGROUND: The interruption of oral anticoagulant (OAC) administration is sometimes indicated in patients with mechanical heart valves, mainly before noncardiac surgery, non-surgical interventions, and pregnancy. Unfractionated heparin (UH) is currently the substitute for selected patients. Low-molecular-weight heparin (LMWH) offers theoretical advantages over UH, but is not currently considered in clinical guidelines as an alternative to UH in patients with prosthetic valves. HYPOTHESIS: The aim of the present study was to review the data accumulated so far on the use of LMWH in this patient population and to discuss its applicability in common practice. METHODS: For this paper, the current medical literature on LMWH in patients with mechanical heart valves was extensively reviewed. RESULTS: There were eight series and six case reports. None of the studies was randomized, and only one was prospective. Data to establish the thromboembolic risk were incomplete. After excluding case reports, the following groups were constructed: (a) short-term administration, after valve insertion (n = 212); (b) short-term, perioperative (noncardiac)/periprocedural (n = 114); (c) long-term, due to intolerance to OAC (n = 16); (d) long-term, in pregnancy (n = 10). The incidence rate of thromboembolism was 0.9% for all the studies and 0.5, 0, 20, and 0% in groups a, b, c, and d, respectively; for hemorrhage, the overall rate was 3.4% (3.8, 2.6, 10, and 0% for the respective groups). CONCLUSIONS: In patients with mechanical heart valves, short-term LMWH therapy compares favorably with UH. Data on mid- and long-term LMWH administration in these patients are sparse. Further randomized studies are needed to confirm the safety and precise indications for the use of LMWH in patients with mechanical heart valves.