A prospective study of Rivaroxaban for central venous catheter associated upper extremity deep vein thrombosis in cancer patients (Catheter 2).

INTRODUCTION: Patients with cancer are at increased risk of thrombosis, particularly those with central venous catheter (CVC) placement, which may predispose to the development of upper extremity deep vein thrombosis (UEDVT). Standard treatment includes low molecular weight heparin (LMWH) or LMWH bridged to warfarin. The direct oral anticoagulants (DOACs) have become standard of care for uncomplicated venous thromboembolism (VTE), but research in patients with cancer is ongoing. OBJECTIVES: To assess rivaroxaban monotherapy in patients with cancer who develop UEDVT due to CVC for preservation of line function, and safety outcomes of VTE recurrence, bleeding risk and death. MATERIALS AND METHODS: Patients ≥18years of age with active malignancy and symptomatic proximal UEDVT with or without pulmonary embolism (PE), associated with a CVC, were eligible. Treatment included rivaroxaban 15mg oral twice daily for 3weeks, followed by 20mg oral daily for 9weeks. Patients were followed clinically for 12weeks to assess for line function, recurrent VTE and bleeding. RESULTS: Seventy patients (47 women) were included, with mean age 54.1years. The most common malignancy was breast cancer (41%). Preservation of line function was 100% at 12weeks. The risk of recurrent VTE at 12weeks was 1.43%, with one episode of fatal PE. 9 patients (12.9%) experienced 11 total bleeding episodes. CONCLUSIONS: Rivaroxaban showed promise in treating CVC-UEDVT in cancer patients, resulting in preserved line function. However, bleeding rates and a fatal pulmonary embolism on treatment are concerning safety outcomes necessitating further study before rivaroxaban can be recommended.

Association between remote major venous thromboembolism risk factors and the risk of recurrence after a first unprovoked episode.

Essentials Is remote exposure to major venous thromboembolism (VTE) risk factor related to lower recurrence? We analyzed data from the REVERSE study, a cohort of patients with no recent major risk factor. We found no association between remote risk factors and the risk of recurrence. Patients with remote VTE risk factor should be managed as having had an unprovoked VTE. SUMMARY: Background It has been shown that the risk of recurrence of venous thromboembolism (VTE) is significantly lower when provoked by a major risk factor such as surgery or trauma compared with an event that was unprovoked. Objectives In this study we aimed to assess the association between remote exposure (3-12 months prior to VTE) to major VTE risk factors and the risk of recurrent VTE. Methods This was a post-hoc analysis of the REVERSE study, a prospective cohort of 646 patients with a first VTE, not provoked by a recent (< 3 months) major risk factor. Results We found no difference in the recurrence rate in patients with or without remote exposure to major VTE risk factors, including immobilization (hazard-ratio [HR], 1.4; 95% confidence interval, 0.7-2.6), surgery (HR, 0.8; 0.3-1.9) and trauma (HR, 1.3; 0.5-3.6). Conclusion None of the tested risk factors were associated with a lower risk of recurrence during follow-up. Patients with remote exposure to major risk factors at the time of a first VTE should not be managed differently from patients with no VTE risk factors.

Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study.

BACKGROUND: Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE. METHODS: Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12. FINDINGS: Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding. CONCLUSION: Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study.

BACKGROUND: Guidelines for perioperative warfarin management in patients with venous thromboembolic disease (VTE) are largely based on expert opinion. OBJECTIVES: To assess the effectiveness and safety of a conservative perioperative anticoagulation strategy in patients with VTE on chronic warfarin therapy. Our center uses a conservative bridging approach for chronic VTE patients consisting of withholding warfarin for 5 days preoperatively, with prophylactic low-molecular-weight heparin (LMWH) post-procedure only if patients are admitted to hospital. PATIENTS/METHODS: We performed a single-center retrospective cohort study. During the study period (1997-2011) there were 634 procedures in 416 patients that were reviewed for postoperative outcomes at 30 and 90 days. RESULTS: Of the 634 procedures, 156 procedures (24.6%) were completed as inpatients. Pre- and post-procedure LMWH bridging was used in 15 (2.4%) and 152 (24.0%) of all procedures, respectively. The 30-day VTE incidence was 0.32% (95% confidence interval [CI] 0.087-1.14), all non-fatal DVTs. The 30-day incidence of major and total bleeding events was 1.26% (95% CI 0.64-2.47) and 3.00% (95% CI 1.93-4.63), respectively. The all-cause mortality rate was 0.32% (95% CI 0.087-1.14) at 30 days; two patients died from arterial thrombosis events. CONCLUSIONS: A randomized controlled trial is needed to provide definitive conclusions but a conservative bridging approach appears promising.

Ambulatory management of pulmonary embolism: a pragmatic evaluation.

BACKGROUND: Patients diagnosed with pulmonary embolism should be considered for treatment on an outpatient basis; however, this practise is not accepted in many centers. OBJECTIVES: Review the safety and efficacy of ambulatory management of patients with pulmonary embolism at our institution. PATIENTS/METHODS: This was a retrospective single center cohort study of consecutive patients diagnosed with idiopathic or secondary pulmonary embolism between January 2003 and January 2008 at the London Health Sciences Centre in London, Ontario, Canada. Patients were eligible for outpatient management of pulmonary embolism if they were hemodynamically stable, did not require oxygen therapy, did not require parenteral narcotics for pain management, and were not felt to be high risk for a major hemorrhage. Patients were assessed at 3 months for thrombosis recurrence and major bleeding episodes. RESULTS: Six hundred and thirty-nine patients were included in the study, of which 314 (49.1%; 95% CI 45.2, 53.1) were managed as outpatients; among these there were three (0.95%; 95% CI, 0.25, 3) thrombotic recurrences and three hemorrhagic events. There were nine deaths (2.9%; 95% CI, 1.4, 5.6), all due to underlying cancer and all occurring after the first 7 days of treatment. CONCLUSIONS: Outpatient management of uncomplicated pulmonary embolism seems safe and effective in the absence of other indications for hospital admission.

A pilot study of central venous catheter survival in cancer patients using low-molecular-weight heparin (dalteparin) and warfarin without catheter removal for the treatment of upper extremity deep vein thrombosis (The Catheter Study).

BACKGROUND: Central venous catheters in patients with cancer are associated with development of deep vein thrombosis (DVT); however, there is no accepted standard treatment. OBJECTIVES: To assess the safety and effectiveness of a management strategy for central venous catheter-related DVT in cancer patients consisting of dalteparin and warfarin without the need for line removal. PATIENTS/METHODS: Patients older than 18 years of age with an active malignancy and who had symptomatic, acute, objectively documented UEDVT were eligible. Patients were treated with dalteparin 200 IU kg(-1) per day for 5-7 days and warfarin with a target International Normalized Ratio of 2.0-3.0. Patients were followed for 3 months for recurrent venous thromboembolism, major hemorrhage and survival of the central venous catheter. RESULTS: There were 74 patients (48 males). The average age was 58 years. There were no episodes of recurrent venous thromboembolism and three (4%) major bleeds. No lines were removed because of infusion failure or recurrence/extension of DVT. CONCLUSION: Treatment of UEDVTs secondary to central catheters in cancer patients with standard dalteparin/warfarin can allow the central line to remain in situ with little risk of line failure or recurrence/extension of the DVT.

Frequency of renal impairment, advanced age, obesity and cancer in venous thromboembolism patients in clinical practice.

BACKGROUND: Low-molecular-weight heparin (LMWH) dosed by weight is recommended as first-line therapy for the initial treatment of venous thromboembolism (VTE) and as monotherapy for long-term treatment of cancer-related VTE. In 'special populations' such as those with renal impairment or the elderly, weight-based dosing may be excessive, and capping the dose in obese patients may lead to inadequate dosing. OBJECTIVES: We determined the frequency of 'special population' characteristics (renal impairment, advanced age, obesity) and cancer among VTE patients in clinical practice, and assessed whether these characteristics appeared to influence the type and dose of anticoagulants prescribed. METHODS: During 2004-2005, among consecutive patients with VTE at two large Canadian hospitals, the proportions with the above characteristics were calculated and treatments prescribed were determined. RESULTS: Of 524 VTE patients, 31% were aged > 75 years. Moderate renal impairment [creatinine clearance (CrCl) 30-59 mL min(-1)] was present in 20% of patients, and severe renal impairment (CrCl < 30 mL min(-1)) in 5% of patients. LMWH was prescribed to 67% of patients with severe renal impairment and to 83% of patients with moderate renal impairment. Body weight was > 100 kg in 15% of patients. Underdosing of LMWH by > 10% was documented in 36% of such patients compared with 8% of patients < 100 kg (P < 0.001). Among 26% of patients with active cancer, only one-third were prescribed LMWH monotherapy. CONCLUSIONS: In clinical practice, renal impairment, advanced age, obesity and cancer are frequently present in patients with VTE. A considerable proportion of these patients may not receive the optimal type or dose of medication to treat VTE.

Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study.

BACKGROUND: Although hormone replacement therapy (HRT) is associated with an increased risk of deep vein thrombosis (DVT), it is not clear if the risk differs in users of combined estrogen-progestin HRT and estrogen-only HRT. METHODS: We prospectively studied postmenopausal women with suspected DVT in whom HRT use status was ascertained and who subsequently had objective diagnostic testing to confirm or exclude DVT. Cases were patients with idiopathic DVT, in whom there were no DVT risk factors, and controls were patients without DVT, in whom there were also no DVT risk factors. The risk of DVT was determined in users of estrogen-progestin HRT and estrogen-only HRT by comparing the prevalence of current HRT use in cases with idiopathic DVT and controls without DVT (reference group). Multivariable regression analysis was done to adjust for factors that might confound an association between HRT use and the risk of DVT. RESULTS: One thousand one hundred and sixty-eight postmenopausal women with suspected DVT were assessed, from whom 95 cases of idiopathic DVT and 610 controls without DVT and no DVT risk factors were identified. Estrogen-only HRT was associated with an increased risk for DVT that was not statistically significant [odds ratio (OR) = 1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-progestin HRT was associated with a greater than 2-fold increased risk for DVT (OR = 2.70; 95% CI 1.44, 5.07). CONCLUSION: The risk of developing DVT may be higher in users of combined estrogen-progestin HRT than in users of estrogen-only HRT.

The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients.

Data evaluating the safety of using weight-based low-molecular-weight heparin in the treatment of obese patients with acute venous thromboembolism are limited. The product monograph of dalteparin suggests the maximum dose should be limited to 18,000 U subcutaneously once daily. There are no specific data regarding the risk of recurrence or bleeding in patients given dalteparin in a weight-based dose of 200 IU kg(-1). We report a retrospective chart review of 193 obese patients who weighed more than 90 kg and who received dalteparin at or near to 200 IU kg(-1) actual body weight for 5-7 days for acute venous thromboembolism with 90 day follow-up information. Of the patients, 77% had idiopathic venous thromboembolism, 16% had an underlying malignancy, and 7% had a transient risk factor. Warfarin was initiated within 2 days with a target International Normalized Ratio range of 2.0-3.0. All patients were followed for 12 weeks post diagnosis. Only two patients had a major hemorrhage, 4 and 8 weeks from diagnosis. This study supports the safety of dosing dalteparin based on actual body weight in obese patients.

Single-arm study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin.

BACKGROUND: When warfarin is interrupted for surgery, low-molecular-weight heparin is often used as bridging therapy. However, this practice has never been evaluated in a large prospective study. This study was designed to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital. METHODS AND RESULTS: This was a prospective, multicenter, single-arm cohort study of patients at high risk of arterial embolism (prosthetic valves and atrial fibrillation with a major risk factor). Warfarin was held for 5 days preoperatively. Low-molecular-weight heparin was given 3 days preoperatively and at least 4 days postoperatively. Patients were followed up for 3 months for thromboembolism and bleeding. Eleven Canadian tertiary care academic centers participated; 224 patients were enrolled. Eight patients (3.6%; 95% CI, 1.8 to 6.9) had an episode of thromboembolism, of which 2 (0.9%; 95% CI, 0.2 to 3.2) were judged to be due to cardioembolism. Of these 8 episodes of thromboembolism, 6 occurred in patients who had warfarin deferred or withdrawn because of bleeding. There were 15 episodes of major bleeding (6.7%; 95% CI, 4.1 to 10.8): 8 occurred intraoperatively or early postoperatively before low-molecular-weight heparin was restarted, 5 occurred in the first postoperative week after low-molecular-weight heparin was restarted, and 2 occurred well after low-molecular-weight heparin was stopped. There were no deaths. CONCLUSIONS: Bridging therapy with subcutaneous low-molecular-weight heparin is feasible; however, the optimal approach for the management of patients who require temporary interruption of warfarin to have invasive procedures is uncertain.

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy.

PURPOSE: The optimal management of patients who have recurrent thromboembolism while being treated with oral anticoagulation therapy is unknown. This study reports managing such patients with extended duration low molecular weight heparin therapy. SUBJECTS AND METHODS: This study was a retrospective review of the prospective databases of three tertiary care teaching hospitals over a 27-month period. All patients who had recurrent symptomatic thromboembolism while being treated with warfarin were identified. All patients were treated with low molecular weight heparin (dalteparin), 200 U/kg daily. Data were collected for recurrent venous thromboembolism, bleeding, and survival. RESULTS: Eight hundred eighty-seven patients were managed for acute thromboembolism. In 32 patients, symptomatic, objectively documented thromboembolism recurred while they were taking warfarin; 63% of the patients with recurrence had cancer, compared with 30% of patients without recurrence. All recurrences were treated with dalteparin. In 3 patients (9% [95% confidence interval: 2% to 25%]), symptomatic recurrence developed while they were being treated with low molecular weight heparin. Nineteen patients (59%) died while receiving anticoagulation therapy; all deaths but 1 were due to malignancy, and none was due to pulmonary embolism or bleeding. CONCLUSIONS: These results suggest that recurrent venous thromboembolism is more likely to develop in cancer patients while being treated with warfarin and that long-term therapy with low molecular weight heparin may be effective in managing warfarin-failure thromboembolic disease.

Dalteparin as periprocedure anticoagulation for patients on warfarin and at high risk of thrombosis.

BACKGROUND: Patients taking warfarin and at high risk for thromboembolic complications have traditionally been hospitalized for two to three days to receive standard treatment with intravenous heparin both prior to and following procedures while their international normalized ratio (INR) is subtherapeutic. OBJECTIVE: To assess the feasibility of protocol implementation for outpatient anticoagulation with low-molecular-weight heparin to eliminate or reduce the length of hospital admission needed solely for anticoagulation. METHODS: Patients included were receiving warfarin for a prosthetic heart valve, mitral valve disease with atrial fibrillation, or recent episode of venous thromboembolism. Warfarin was discontinued four days prior to the procedure. Subcutaneous dalteparin 200 units/kg was given on the two mornings prior to the procedure and restarted 12-24 hours after the procedure until the INR was in the therapeutic range. Warfarin was reinitiated on the evening of surgery. RESULTS: Twenty-four patients underwent 26 procedures. There were two minor bleeding complications, and one patient experienced a transient ischemic attack. Patients received a median of five days of dalteparin. The INR returned to the therapeutic range on the median postoperative day 4. All patients avoided two days of hospitalization prior to the procedure (i.e., no patients needed to be admitted preoperatively for anticoagulation). A median of four days would have been required for the sole purpose of postoperative anticoagulation. CONCLUSIONS: Outpatient perioperative anticoagulation with dalteparin for high-risk patients requiring long-term oral anticoagulation appears feasible and warrants further study.

A latex D-dimer reliably excludes venous thromboembolism.

BACKGROUND: D-Dimer, a cross-linked fibrin degradation product, has a high sensitivity in patients with suspected venous thrombosis. Traditional latex D-dimer assays, however, have not been sufficiently sensitive to exclude venous thromboembolism. METHODS: To determine the clinical utility of a latex D-dimer assay (MDA D-Dimer; Organon Teknika Corporation, Durham, NC) in patients with suspected venous thromboembolism, we conducted a retrospective cohort study involving 595 unselected patients at 4 tertiary care hospitals. Patients had blood drawn for performance of the D-dimer assay and underwent objective testing for venous thromboembolism. Pretest probability was determined using validated models in 571 patients. Patients were classified as venous thromboembolism positive or negative according to results of objective tests and 3-month follow-up. The sensitivities, specificities, predictive values, and negative likelihood ratios of the assay were calculated for all patients and for subgroups of patients with known cancer or a low, moderate, or high pretest probability of venous thromboembolism. RESULTS: The prevalence of venous thromboembolism was 19.0% (113/595). Of those who had a pretest probability assessment, 35.9% had a low pretest probability, 49.7% a moderate pretest probability, and 14.4% a high pretest probability. Using a discriminant value of 0.50 microg fibrinogen equivalent units per milliliter, the assay showed an overall sensitivity of 96%, a negative predictive value of 98%, a specificity of 45%, and a negative likelihood ratio of 0.09. In patients with a low or moderate pretest probability, the sensitivity, negative predictive value, and negative likelihood ratio were 97%, 99%, and 0.07, respectively. CONCLUSIONS: The MDA D-Dimer assay is the first latex agglutination assay with sufficient sensitivity to be clinically useful in the exclusion of venous thromboembolism. A negative result has the potential to be used as the sole test to exclude venous thromboembolism in patients with a low or moderate pretest probability of disease.

Acquired factor VIII inhibitor in a patient with chronic myelogenous leukemia receiving interferon-alfa therapy.

OBJECTIVE: To report a case of an acquired factor VIII inhibitor associated with the use of interferon-alfa. CASE SUMMARY: A 58-year-old white man with newly diagnosed chronic myelogenous leukemia (CML) was initially treated with hydroxyurea. Interferon-alfa therapy was started six weeks later in order to enhance the response, with gradual reduction and eventual discontinuation of hydroxyurea. Interferon-alfa was continued for one year. Following bone marrow aspiration at one year, the patient developed significant bleeding and bruising at the site of extraction. His hemoglobin decreased from 11.3 to 9.3 g/dL and his activated partial thromboplastin time was elevated at 72 seconds. The factor VIII concentration was 0.02 units/mL; factor VIII inhibitor concentration was 58 Bethesda units. A diagnosis of an acquired factor VIII inhibitor was made, and the patient was treated with activated factor VII concentrates and prednisone. Interferon-alfa was discontinued, and the inhibitor subsequently disappeared over the next six weeks. The patient did not have any further bleeding problems. DISCUSSION: Acquired factor VIII inhibitors other than in patients with hemophilia are rare. To date, there are no reported cases of factor VIII inhibitors associated with CML. Moreover, the temporal association with interferon-alfa administration suggests a causal relationship. There are only two previous case reports suggesting interferon-alfa as a cause of factor VIII inhibitors. CONCLUSIONS: Induction of factor VIII inhibitors is a serious potential complication of therapy with interferon-alfa. We suggest that a diagnosis of an acquired factor VIII inhibitor be considered in patients who experience unexplained bleeding with interferon-alfa therapy.

Outpatient use of low molecular weight heparin (Dalteparin) for the treatment of deep vein thrombosis of the upper extremity.

Upper extremity deep vein thrombosis (DVT) is now recognized as a major cause of morbidity and mortality. There is little information regarding the most effective treatment of this condition. We report a prospective cohort study of the use of low molecular weight heparin (LMWH) in the outpatient management of upper extremity DVT. Forty-six patients were managed as outpatients for objectively documented upper extremity DVT with dalteparin (200 aXa u/kg), for a minimum of five days. Warfarin was usually initiated on the first day with a target INR of 2.0-3.0. Most patients had an underlying malignancy or a history of a central line. All patients were followed for 12 weeks from diagnosis. Only one patient had a major bleed. No patients developed pulmonary emboli. One patient had a recurrence of DVT during the treatment with LMWH with extension of the existing thrombus. Seven patients died, all due to their underlying disease. This study supports the safety and effectiveness of dalteparin in the treatment of upper extremity DVT. Given that these patients were treated as outpatients, there is a potential for huge cost savings.

Body weight does not predict for anti-Xa levels after fixed dose prophylaxis with enoxaparin after orthopedic surgery.

Enoxaparin after joint arthroplasty is effective prophylaxis against venous thromboembolism. This is usually given as a fixed dose without monitoring of anti-Xa levels. This study assesses the relationship between trough anti-Xa levels, body weight, and venous thromboembolism. Consenting patients at three institutions were treated with Enoxaparin 30 mg subcutaneously bis in die postoperatively until discharge. Chromogenic anti-Xa levels were measured on the fifth postoperative day by the method of Stachrome (Diagnostica Stago). All patients had bilateral compression doppler ultrasonography on day 10 or discharge and were followed for 12 weeks for evidence of venous thromboembolism. Eleven patients developed objectively confirmed venous thromboembolism during the study. In this study, there was poor correlation between weight and anti-Xa levels. In addition, body weight and anti-Xa levels of patients who developed venous thromboembolism were compared to those who did not and there were no significant differences between the two groups. In conclusion, this study shows that there is poor correlation of trough anti-Xa levels with body weight. Recognizing the low overall event rate this study does not support the need to monitor anti-Xa levels or adjusting the dose according to weight.

Myoclonus due to chlorambucil in two adults with lymphoma.

OBJECTIVE: To report myoclonus due to chlorambucil therapy in two adults with lymphoma, and to review the literature of chlorambucil neurotoxicity in adults. CASE SUMMARIES: Case 1: An 81-year-old man with lymphoma being treated with chlorambucil developed jerking movements and stiffness that persisted for 3 days and intensified at night. The dosage of chlorambucil was decreased with a subsequent decrease in symptomatology. Resolution of the myoclonus occurred with discontinuation of the chlorambucil. Rechallenge evoked a return of tremors the next day that later became constant and again resolved on discontinuation of chlorambucil. Case 2: A 75-year-old woman with lymphoma being treated with chlorambucil developed jerking movements in her limbs, particularly in her arms and right hip. The symptoms were so severe they prevented the patient from leaving her house. All symptoms resolved within 2-3 days after the cycle was completed and did not return. She was diagnosed as having had chlorambucil-induced myoclonus. DATA SOURCES: Searches were performed on MEDLINE, CancerLit, and Science Citation Index Review to identify reports and articles discussing chlorambucil-induced neurotoxicity, particularly myoclonus. DISCUSSION: Chlorambucil-induced myoclonus has been described in overdose situations and in the treatment of nephrotic syndrome in children. Three cases of reversible myoclonic activity associated with high-dose chlorambucil in adults have also been described. In each case, the myoclonus resolved following discontinuation of the drug. Only one other conclusive case of low-dose chlorambucil-induced myoclonus in an adult has been described. The two cases presented here are unique in that the myoclonus occurred in adults receiving low-dose chlorambucil who had no myoclonus before or after treatment with the drug. CONCLUSIONS: From the cases reviewed, it appears that chlorambucil may induce myoclonus in adults receiving therapeutic dosages of chlorambucil. The neurologic status of patients receiving chlorambucil should be followed closely during treatment. If myoclonus develops, drug-induced myoclonus should be considered, as well as discontinuation of the drug.

Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group.

BACKGROUND: Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. METHODS: Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration > or = 12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. RESULTS: Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P < 0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was tolerated well. CONCLUSIONS: Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.