Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial.

BACKGROUND: The AMPLIFY trial compared apixaban with enoxaparin followed by warfarin for the treatment of acute venous thromboembolism (VTE). OBJECTIVE: To perform a subgroup analysis to compare the efficacy and safety of apixaban and enoxaparin followed by warfarin for the treatment of VTE in patients with cancer enrolled in AMPLIFY. PATIENTS/METHODS: Patients with symptomatic VTE were randomized to a 6-month course of apixaban or enoxaparin followed by warfarin. The primary efficacy outcome and principal safety outcome were recurrent VTE or VTE-related death and major bleeding, respectively. RESULTS: Of the 5395 patients randomized, 169 (3.1%) had active cancer at baseline, and 365 (6.8%) had a history of cancer without active cancer at baseline. Among patients with active cancer, recurrent VTE occurred in 3.7% and 6.4% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (relative risk [RR] 0.56, 95% confidence interval [CI] 0.13-2.37); major bleeding occurred in 2.3% and 5.0% of evaluable patients, respectively (RR 0.45, 95% CI 0.08-2.46). Among patients with a history of cancer, recurrent VTE occurred in 1.1% and 6.3% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (RR 0.17, 95% CI 0.04-0.78); major bleeding occurred in 0.5% and 2.8% of treated patients, respectively (RR 0.20, 95% CI 0.02-1.65). CONCLUSIONS: The results of this subgroup analysis suggest that apixaban is a convenient option for cancer patients with VTE. However, additional studies are needed to confirm this concept and to compare apixaban with low molecular weight heparin in these patients.

Thrombosis: a major contributor to global disease burden.

BACKGROUND: Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. OBJECTIVE: To review the literature on the global burden of disease caused by VTE. APPROACH AND RESULTS: We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. CONCLUSIONS: VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden.

Comparison of idrabiotaparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: the Borealis-Atrial Fibrillation Study.

BACKGROUND: Idrabiotaparinux, a long-acting inhibitor of factor Xa, was shown to be effective in the treatment of patients with venous thromboembolism. OBJECTIVE: To assess non-inferiority for the efficacy of idrabiotaparinux versus warfarin in patients with atrial fibrillation (AF) at risk of stroke and systemic embolism. Bleeding was also assessed. METHODS: This randomized, double-blind trial enrolled patients with electrocardiogram-documented AF. Idrabiotaparinux was administered weekly via subcutaneous injection, and warfarin was administered daily with dose adjustment to maintain the international normalized ratio between 2.0 and 3.0. Each idrabiotaparinux injection was 3 mg for the first 7 weeks, followed by 2 mg thereafter, except in patients with a creatinine clearance of 30-50 mL min(-1) or aged ≥ 75 years. The patients received 1.5 mg after the first 7 weeks. The efficacy outcome was the composite of all fatal or non-fatal strokes and systemic embolism. The safety outcome was clinically relevant bleeding (major and clinically relevant non-major bleeding). RESULTS: The study was terminated prematurely by the sponsor for strategic/commercial, not scientific, reasons, with 39% of the planned number of patients included and an average duration of treatment of 240 days. Of the 1886 idrabiotaparinux recipients, 20 developed stroke or systemic embolism (1.5% per year), whereas this occurred in 22 of the 1887 warfarin patients (1.6% per year, hazard ratio 0.98, 95% confidence interval 0.49-1.66). The annual incidence of bleeding was 6.1% in the idrabiotaparinux and 10.0% in the warfarin group (hazard ratio 0.61, 95% confidence interval 0.46-0.81). CONCLUSION: If anything, despite its early termination, the idrabiotaparinux regimen studied suggested a comparable efficacy to dose-adjusted warfarin, with a lower bleeding risk.

Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.

BACKGROUND: New oral anticoagulants for thromboprophylaxis after hip or knee arthroplasty have been given as fixed-dose regimens. OBJECTIVE: To evaluate the consistency of the antithrombotic efficacy and bleeding risk of apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily after knee or hip arthroplasty across the clinical characteristics of age, gender, body weight, body mass index (BMI) and creatinine clearance. METHODS: The pooled results of the ADVANCE-2 (knee arthroplasty) and -3 (hip arthroplasty) randomized trials were used to evaluate if treatment had a statistically significantly different effect (P < 0.10) on major venous thromboembolism (VTE) and bleeding for the characteristics of age, gender, body weight, BMI and creatinine clearance. Both univariate analysis and multivariate logistic regression were used. RESULTS: Univariate analyses identified statistically significant interactions for age and major VTE (P = 0.09); for both age (P = 0.07) and body weight (P = 0.07) and the outcome of major bleeding; and for creatinine clearance (P = 0.03) and the composite outcome of major and clinically relevant non-major bleeding. Estimates of these possible differences were not precise, with wide 95% confidence intervals (CIs) that included a zero difference for several subgroups. Multivariate logistic regression analysis did not detect a statistically significant interaction for any outcomes. CONCLUSIONS: This analysis found no convincing evidence that age, weight, gender, BMI or creatinine clearance influenced the balance of benefit to risk for apixaban compared with enoxaparin. Because only 5% of patients had a creatinine clearance between 30 and 50 mL min(-1), further data are needed in such patients.

Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials.

In order to compare the effect of oral apixaban (a factor Xa inhibitor) with subcutaneous enoxaparin on major venous thromboembolism and major and non-major clinically relevant bleeding after total knee and hip replacement, we conducted a pooled analysis of two previously reported double-blind randomised studies involving 8464 patients. One group received apixaban 2.5 mg twice daily (plus placebo injection) starting 12 to 24 hours after operation, and the other received enoxaparin subcutaneously once daily (and placebo tablets) starting 12 hours (± 3) pre-operatively. Each regimen was continued for 12 days (± 2) after knee and 35 days (± 3) after hip arthroplasty. All outcomes were centrally adjudicated. Major venous thromboembolism occurred in 23 of 3394 (0.7%) evaluable apixaban patients and in 51 of 3394 (1.5%) evaluable enoxaparin patients (risk difference, apixaban minus enoxaparin, -0.8% (95% confidence interval (CI) -1.2 to -0.3); two-sided p = 0.001 for superiority). Major bleeding occurred in 31 of 4174 (0.7%) apixaban patients and 32 of 4167 (0.8%) enoxaparin patients (risk difference -0.02% (95% CI -0.4 to 0.4)). Combined major and clinically relevant non-major bleeding occurred in 182 (4.4%) apixaban patients and 206 (4.9%) enoxaparin patients (risk difference -0.6% (95% CI -1.5 to 0.3)). Apixaban 2.5 mg twice daily is more effective than enoxaparin 40 mg once daily without increased bleeding.

Effect of obesity on outcomes after fondaparinux, enoxaparin, or heparin treatment for acute venous thromboembolism in the Matisse trials.

BACKGROUND: Selecting initial anticoagulant dose by patient weight for acute pulmonary embolism and deep vein thrombosis has clinical credibility; however, uncertainty remains regarding how to dose obese patients with newer anticoagulants because outcome data are sparse. OBJECTIVES: To use the Matisse trials' comparison of sc fondaparinux once daily with control heparin therapies (intravenous unfractionated heparin for pulmonary embolism, sc enoxaparin 1 mg/kg b.i.d. for deep vein thrombosis) for initial treatment in order to compare primary outcomes (venous thromboembolism recurrence and major bleeding) in obese patients. PATIENTS AND METHODS: Primary outcomes were compared in subsets composed of patients weighing < or = and > 100 kg and with body mass index (BMI) < 30 and > or = 30 kg/m(2). Medians and ranges for weight and BMI were compared for patients suffering either recurrence or major bleeding. RESULTS: Twenty-two thousand and one patients received fondaparinux and 2217 received enoxaparin or unfractionated heparin. Four hundred and ninety-six patients (11%) weighed > 100 kg and 1216 (28%) had a BMI > or = 30. Treatment groups had similar characteristics. The upper limit in subject weight for recurrence was 166 kg (BMI 58), and for major bleeding 120 kg (BMI 39). The incidences of recurrence and major bleeding were similar for each patient subset of weight and BMI for both fondaparinux and heparin treatment groups. Among patients with a primary outcome, median weights and BMIs were also similar. CONCLUSIONS: The current recommended doses of fondaparinux and heparins for the treatment of venous thromboembolism appear to provide similar protection against recurrence and major bleeding to one another and to obese and non-obese patients.

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

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

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

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

Withholding treatment in patients with acute pulmonary embolism who have a high risk of bleeding and negative serial noninvasive leg tests.

PURPOSE: Patients who have nonmassive acute pulmonary embolism and a high risk of bleeding or contraindication to anticoagulants, such recent surgery or gastrointestinal bleeding, present a clinical dilemma. We sought to estimate whether such patients could be safely left untreated if serial compression ultrasound or serial impedance plethysmography were negative and cardiorespiratory reserve was adequate. SUBJECTS AND METHODS: The frequency of recurrent pulmonary embolism among patients with nonmassive acute pulmonary embolism and negative serial noninvasive leg tests who were not treated was estimated from two prospective studies of the noninvasive management of patients with suspected pulmonary embolism. One of the studies used serial impedance plethysmography of the lower extremities; the other used serial compression ultrasound. The prevalence of pulmonary embolism in patients with nondiagnostic ventilation/perfusion lung scans was determined from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). RESULTS: The estimated frequency of fatal recurrent pulmonary embolism was 1% [95% confidence interval (CI), 0% to 5%) among untreated patients with nonmassive pulmonary embolism who had negative serial impedance plethysmograms and 0% (95% CI, 0% to 4%) among those with negative serial compression ultrasonograms. The frequency of nonfatal recurrent pulmonary embolism among untreated patients was 3%, regardless of whether they had negative serial impedance plethysmograms or negative serial compression ultrasonograms. These results were comparable with the frequency of recurrent pulmonary embolism among patients treated with anticoagulants or with inferior vena cava filters. CONCLUSION: Withholding treatment of nonmassive acute pulmonary embolism, if serial impedance plethysmograms or serial venous ultrasonograms are negative and cardiopulmonary reserve is adequate, is a possible strategy for the management of patients with a high risk of bleeding or other contraindication to anticoagulants. This strategy may be associated with fewer adverse events than treatment with anticoagulants or an inferior vena cava filter. Prospective trials comparing alternative treatments are needed.

Predictive value of compression ultrasonography for deep vein thrombosis in symptomatic outpatients: clinical implications of the site of vein noncompressibility.

BACKGROUND: Compression ultrasonography has a high negative predictive value for deep vein thrombosis in symptomatic outpatients. Limited data are available on factors influencing positive predictive value. The objective of this study was to evaluate the positive predictive value of compression ultrasonography according to the anatomic site of vein noncompressibility. METHODS: We performed a prospective cohort study of 756 consecutive outpatients with suspected first-episode deep vein thrombosis. Compression ultrasonography was performed at the initial visit: results were abnormal if a noncompressible segment was identified or normal if all segments were fully compressible. Venography was performed in patients with abnormal compression ultrasonography results. Positive predictive value was determined according to the site of noncompressibility: common femoral vein only, popliteal vein only, or both sites. Venography was the reference standard for the presence of deep vein thrombosis. RESULTS: Positive predictive value was 16.7% (95% confidence interval, 0.4%-64.1%) for noncompressibility isolated to the common femoral vein compared with 91.3% (95% confidence interval, 72.0%-98.9%) for the popliteal vein only and 94.4% (95% confidence interval, 72.7%-99.9%) for both sites (P<.001). Of 15 patients with isolated noncompressibility of the common femoral vein, 8 (53%) had pelvic neoplasm or abscess compared with 2 (5%) of 42 with noncompressibility of the popliteal vein only and 6 (13%) of 47 with noncompressibility of both sites (P<.001). CONCLUSIONS: The positive predictive value of noncompressibility isolated to the common femoral vein is too low to be used alone as the diagnostic end point for giving anticoagulant therapy. Noncompressibility isolated to the common femoral vein is a diagnostic marker for pelvic disease.

Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group.

BACKGROUND: Pulmonary embolism (PE) occurs in 50% or more of patients with proximal deep-vein thrombosis. Low-molecular-weight heparin treatment is effective and safe in patients with deep vein thrombosis and may also be so in patients with PE. Recent rigorous clinical trials have established objective criteria for determining a high probability of PE by perfusion lung scanning. OBJECTIVE: To compare low-molecular-weight heparin with intravenous heparin for the treatment of patients with objectively documented PE and underlying proximal deep vein thrombosis. METHODS: In a multicenter, double-blind, randomized trial, we compared fixed-dose subcutaneous low-molecular-weight heparin (tinzaparin sodium) given once daily with dose-adjusted intravenous heparin given by continuous infusion using objective documentation of clinical outcomes. Pulmonary embolism at study entry was documented by the presence of high-probability lung scan findings. RESULTS: Of 200 patients with high-probability lung scan findings at study entry, none of the 97 who received low-molecular-weight heparin had new episodes of venous thromboembolism compared with 7 (6.8%) of 103 patients who received intravenous heparin (95% confidence interval for the difference, 1.9%-11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1 patient (1.0%) who was given low-molecular-weight heparin and in 2 patients (1.9%) given intravenous heparin (95% confidence interval for the difference, -2.4% to 4.3%). CONCLUSIONS: Low-molecular-weight heparin administered once daily subcutaneously was no less effective and probably more effective than use of dose-adjusted intravenous unfractionated heparin for preventing recurrent venous thromboembolism in patients with PE and associated proximal deep vein thrombosis. Our findings extend the use of low-molecular-weight heparin without anticoagulant monitoring to patients with submassive PE.

Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review.

PURPOSE: To determine the sensitivity and specificity of helical computed tomography (CT) for the diagnosis of pulmonary embolism and to determine the safety of withholding anticoagulant therapy in patients who have clinically suspected pulmonary embolism and negative results on helical CT. DATA SOURCES: The MEDLINE database was searched for all reports published from 1986 to October 1999 that evaluated the use of helical CT for the diagnosis of pulmonary embolism. Bibliographies of the retrieved articles were cross-checked to identify additional studies. STUDY SELECTION: All prospective English-language studies were selected. Retrospective studies, review articles, and case reports were excluded, and 5 of the 20 identified articles were excluded. The scientific validity of the remaining 15 articles was assessed. DATA EXTRACTION: Two of the authors used a priori, pre-defined criteria to independently assess each study. A third author resolved disagreements by adjudication. The pre-defined criteria were inclusion of a consecutive series of all patients with suspected pulmonary embolism, inclusion of patients with and those without pulmonary embolism, a broad spectrum of patient characteristics, performance of helical CT and pulmonary angiography (or an appropriate reference test) in all patients, and independent interpretation of the CT scan and pulmonary angiogram (or reference test). Specific data on sensitivity and specificity and the associated 95% CIs were recorded when available. DATA SYNTHESIS: No study met all of the predefined criteria for adequately evaluating sensitivity and specificity. The reported sensitivity of helical CT ranged from 53% to 100%, and specificity ranged from 81% to 100%. In no prospective study was anticoagulant therapy withheld without further testing for venous thromboembolism in consecutive patients with suspected pulmonary embolism. One prospective study reported the outcome of selected patients with negative results on helical CT who did not receive anticoagulant therapy. CONCLUSIONS: Use of helical CT in the diagnosis of pulmonary embolism has not been adequately evaluated. The safety of withholding anticoagulant treatment in patients with negative results on helical CT is uncertain. Definitive large, prospective studies should be done to evaluate the sensitivity, specificity, and safety of helical CT for diagnosis of suspected pulmonary embolism.

Diagnosis of pulmonary embolism.

The patient with suspected pulmonary embolism presents a challenging diagnostic problem. The symptoms and signs are nonspecific, and objective testing is required to establish or exclude the presence of pulmonary embolism. Lung scanning continues to be a first-line test, but in 40% to 70% of all patients, the results do not definitively provide indication for either giving or withholding anticoagulant treatment even when combined with the clinical assessment. Pulmonary angiography is the reference standard, but it is invasive and may not be available in all clinical settings. Pulmonary embolism is strongly associated with proximal deep-vein thrombosis of the legs (popliteal, femoral, or iliac vein thrombosis). Objective testing for proximal deep-vein thrombosis is useful in patients with suspected pulmonary embolism. A positive result from such testing provides an indication for anticoagulant treatment. Serial testing for proximal deep-vein thrombosis is a safe and effective alternative to pulmonary angiography in patients with adequate cardiorespiratory reserve. The assay for plasma D-dimer using either a rapid enzyme-linked immunospecific assay technique or a bedside whole-blood agglutination technique is promising as a test for excluding venous thromboembolism. A positive result by spiral CT imaging is useful for ruling in a diagnosis of pulmonary embolism, but the safety of withholding treatment in patients with negative spiral CT results remains uncertain. Pulmonary angiography continues to have an important role in selected patients in whom it is critical to definitively confirm or exclude the presence of pulmonary embolism.

Drug-induced thrombocytopenia.

Many drugs can induce thrombocytopenia mediated by drug-dependent antiplatelet antibodies. Recent studies have documented specific epitopes for drug-dependent antibody binding on glycoprotein Ib-IX, glycoprotein IIb-IIIa, and platelet-endothelial cell adhesion molecule-1. Molecular identification of antibody binding sites may help to identify susceptible individuals. Management of patients with unexpected thrombocytopenia who are taking multiple drugs remains a difficult clinical problem. A recent systematic review of all published case reports of drug-induced thrombocytopenia ranks drugs according to the strength of clinical evidence for a causal relation to thrombocytopenia. This database is available online at http://moon.ouhsc.edu/jgeorge.

Heparin and low molecular weight heparin for treatment of acute pulmonary embolism.

Pulmonary embolism occurs in more than 175,000 patients each year in the United States. The objectives of treatment are to prevent death from the existing embolus, to prevent death and morbidity from recurrent pulmonary embolism, and to prevent morbidity from recurrent deep-vein thrombosis. For patients with adequate cardiorespiratory reserve, the primary objective is to prevent recurrent pulmonary embolism. Anticoagulant therapy with intravenous unfractionated heparin or subcutaneous low molecular weight heparin followed by oral anticoagulant treatment for at least 3 months is the treatment of choice for most of these patients. Clinical trials indicate that the effectiveness of intravenous heparin depends on achieving an adequate heparin effect (activated partial thromboplastin time above lower limit) during the initial 24 hours. A validated protocol for intravenous heparin should be used to lessen the likelihood of delayed heparinization. Low molecular weight heparin given subcutaneously either once or twice daily is as effective as intravenous heparin for the treatment of patients with deep-vein thrombosis and submassive pulmonary embolism. Low molecular weight heparin enables many patients with uncomplicated deep-vein thrombosis to be treated in an outpatient setting.

Preoperative vs postoperative initiation of low-molecular-weight heparin prophylaxis against venous thromboembolism in patients undergoing elective hip replacement.

BACKGROUND: Although preoperative and postoperative initiation of prophylaxis for deep vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) are effective, the relative effectiveness and safety of these approaches is unknown. In the absence of a published definitive level 1 trial addressing this question, a meta-analysis is appropriate. OBJECTIVE: To report a meta-analysis comparing preoperative with postoperative initiation of prophylaxis of DVT in patients undergoing elective hip replacement. METHODS: Relevant trials were identified, and potential biases in the meta-analysis were minimized by analyzing all rigorously performed randomized trials that met all of the following criteria for conduct of the trial: (1) double-blind design, (2) objective documentation of the frequencies of DVT by ascending contrast venography, (3) venography performed before or at the time of discharge from the hospital, (4) initiation of the same LMWH preoperatively or postoperatively in dosages shown to be effective, (5) compliance with the criteria for a level 1 trial, and (6) objective documentation of major and minor bleeding according to strict criteria. RESULTS: Treatment with LMWH initiated preoperatively was associated with a DVT frequency of 10.0% compared with a frequency of 15.3% when the LMWH was initiated postoperatively (P = .02, Fisher exact test). Major bleeding was less frequent in patients receiving preoperatively initiated LMWH than in patients receiving postoperatively initiated LMWH (0.9%, vs. 3.5%; P = .01, Fisher exact test). CONCLUSIONS: Our findings support the need for a randomized comparison of preoperative and postoperative initiation of pharmacological prophylaxis of DVT. Such a trial would resolve the divergent practices for DVT prophylaxis between Europe and the North American countries, the United States and Canada, and would affect the treatment for thousands of patients on both continents.

Drug-induced thrombocytopenia: a systematic review of published case reports.

PURPOSE: To determine the strength of clinical evidence for individual drugs as a cause of thrombocytopenia. DATA SOURCES: All English-language reports on drug-induced thrombocytopenia. STUDY SELECTION: Articles describing thrombocytopenia caused by heparin were excluded from review. Of the 581 articles reviewed, 20 were excluded because they contained no patient case reports. The remaining 561 articles reported on 774 patients. DATA EXTRACTION: Two of the authors used a priori criteria to independently review each patient case report. Two hundred fifty-nine patient case reports were excluded from further review because of lack of evaluable data, platelet count of 100000 cells/microL or more, use of cytotoxic or nontherapeutic agents, occurrence of drug-induced systemic disease, or occurrence of disease in children. For the remaining 515 patient case reports, a level of evidence for the drug as the cause of thrombocytopenia was assigned. Data on bleeding complications and clinical course were recorded. DATA SYNTHESIS: The evidence supported a definite or probable causal role for the drug in 247 patient case reports (48%). Among the 98 drugs described in these reports, quinidine was mentioned in 38 case reports, gold in 11, and trimethoprim-sulfamethoxazole in 10. Of the 247 patients described in the case reports, 23 (9%) had major bleeding and 2 (0.8%) died of bleeding. CONCLUSIONS: Many reports of drug-induced thrombocytopenia do not provide evidence supporting a definite or probable causal relation between the disease and the drug. Future patient case reports should incorporate standard criteria to clearly establish the etiologic role of the drug.

Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting.

BACKGROUND: Venous thromboembolism is a common complication of surgery. Although surveys of physician self-reported practices have suggested near universal support for routine use of measures to prevent venous thromboembolism, medical record auditing has demonstrated underuse. OBJECTIVE: To assess physician practices of venous thromboembolism prophylaxis in the community hospital setting. METHODS: Retrospective review of the medical records from 20 hospitals in Oklahoma of 419 Medicare patients aged 65 years or older undergoing major abdominothoracic surgery between April 1 and December 31, 1995. Utilization rates of prophylaxis stratified according to patient risk for venous thromboembolism were measured. RESULTS: Prophylaxis measures were implemented for only 160 (38%) of 419 patients studied (95% confidence interval, 33%-43%). There was little variation in the use of prophylaxis based on the risk for venous thromboembolism. Only 97 (39%) of 250 patients (95% confidence interval, 33%-45%) at very high risk received any form of prophylaxis and of these 97, only 64 patients (66%) received appropriate measures (95% confidence interval, 56%-75%). CONCLUSIONS: Despite widely disseminated, evidence-based recommendations, venous thromboembolism prophylaxis is underused in Medicare patients undergoing major abdominothoracic surgery in community hospitals in Oklahoma.