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.

Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development.

BACKGROUND: A growing health problem, venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), requires refined diagnostic and therapeutic approaches. Neutrophils contribute to thrombus initiation and development in experimental DVT. Recent animal studies recognized neutrophil extracellular traps (NETs) as an important scaffold supporting thrombus stability. However, the hypothesis that human venous thrombi involve NETs has not undergone rigorous testing. OBJECTIVE: To explore the cellular composition and the presence of NETs within human venous thrombi at different stages of development. PATIENTS AND METHODS: We examined 16 thrombi obtained from 11 patients during surgery or at autopsy using histomorphological, immunohistochemical and immunofluorescence analyses. RESULTS: We classified thrombus regions as unorganized, organizing and organized according to their morphological characteristics. We then evaluated them, focusing on neutrophil and platelet deposition as well as micro-vascularization of the thrombus body. We observed evidence of NET accumulation, including the presence of citrullinated histone H3 (H3Cit)-positive cells. NETs, defined as extracellular diffuse H3Cit areas associated with myeloperoxidase and DNA, localized predominantly during the phase of organization in human venous thrombi. CONCLUSIONS: NETs are present in organizing thrombi in patients with VTE. They are associated with thrombus maturation in humans. Dissolution of NETs might thus facilitate thrombolysis. This finding provides new insights into the clinical development and pathology of thrombosis and provides new perspectives for therapeutic advances.

Cost benefit of intermittent pneumatic compression for venous thromboembolism prophylaxis in general surgery.

AIM: In moderate to high-risk general surgical patients, the cost effectiveness of mechanical prophylaxis for venous thromboembolism (VTE) is uncertain. Therefore, we determined the costs and savings of intermittent pneumatic compression (IPC) plus graduated compression stockings (GCS). METHODS: Postoperative VTE events in the absence of prophylaxis, efficacy of prophylaxis and costs of prophylaxis have been obtained from the English literature and Medicare 2004 reimbursement schedule. RESULTS: In 1000 moderate to high risk general surgical patients, in the absence of prophylaxis, the cost of investigating and treating 72 patients with clinical suspicion of DVT and 32 with PE is calculated to be $263,779. This corresponds to a cost of $263 per surgical patient. The cost of IPC combined with TED stockings in 1000 similar patients would be $66 760, and the cost of diagnosis and treatment of the reduced numbers (69% reduction) of clinical VTE is $ 83,574 making a total of $150 344. This means a saving of $133,435 ($263,779 - $150,344) per 1000 patients. This corresponds to a saving of $113 per surgical patient. Sensitivity analysis demonstrates that despite variation in costs or efficacy for IPC plus GCS, marked savings persist. CONCLUSIONS: Prophylaxis with IPC not only prevents VTE but also saves money.

Modern treatment of pulmonary embolism.

Modern treatment of acute pulmonary embolism requires rapid and accurate diagnosis followed by risk stratification to devise an optimal management strategy. Patients at low risk have good outcomes simply with intensive anticoagulation treatment. Higher-risk patients may require more aggressive intervention with thrombolysis or embolectomy. Clinical risk factors for an adverse outcome include increasing age, cancer, congestive heart failure, systemic arterial hypotension, chronic obstructive pulmonary disease and right ventricular dysfunction. A promising approach is the Geneva Prognostic Score, which is based upon a rapid clinical assessment. On physical examination, signs of right ventricular failure, including distended jugular veins and a right-sided S3 gallop, should be looked for. The electrocardiogram may show evidence of right ventricular strain with a new right bundle branch block or T wave inversion in leads V1-V4. The troponin level may be elevated as a marker of cardiac injury and right ventricular microinfarction, even in the absence of coronary artery disease. The most useful imaging marker of high risk is the presence of moderate or severe right ventricular dilatation and hypokinesis on the echocardiogram, especially with progressively worsening right ventricular function despite intensive anticoagulation treatment. Patients at high risk should be considered for thrombolytic therapy or embolectomy rather than management with anticoagulation therapy alone. Special care must be taken to avoid thrombolytic therapy among patients who might be susceptible to intracranial haemorrhage. Intracranial haemorrhage reached a surprisingly high rate of 3.0% in the International Cooperative Pulmonary Embolism Registry of 2,454 prospectively evaluated acute pulmonary embolism patients at 52 hospitals in seven countries. An alternative approach to patients at high risk is a catheter-based or open surgical embolectomy. It is crucial to refer these patients as quickly as possible, rather than delaying intervention until cardiogenic shock has ensued. Fortunately the current tools for risk stratification provide an "early window" for prognostication and can help the coordination of a definitive treatment plan with optimal results.

Rescue percutaneous coronary intervention immediately following coronary artery bypass grafting.

Perioperative graft failure after coronary artery bypass graft (CABG) can result in acute myocardial infarction with dire clinical consequences. We report a case of rescue percutaneous coronary intervention immediately after unsuccessful CABG. This approach salvaged the patient from cardiogenic shock and should be recognized as a viable alternative to immediate reoperation for certain patients.

Cost implications of low molecular weight heparins as prophylaxis following total hip and knee replacement.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are serious and costly complications of total hip and knee replacement surgery. The risk of these complications is significantly reduced by prophylaxis. Low molecular weight heparins (LMWH) are being used for this indication with increased frequency. The objective of this study was to assess the cost implications of LMWH for the prevention of symptomatic DVT and PE complications following total hip and knee replacement surgery. The study design was cost analysis based on utilization and the costs of medical resources for prophylaxis and treatment of DVT/PE. A retrospective hospital data set was used to assess symptomatic DVT/PE complication rates and medical resource utilization in patients receiving warfarin, other, and no prophylaxis. The results of a clinical trial were used to estimate relative reductions in risk of symptomatic DVT/PE due to prophylaxis with LMWH. The 7721 total hip and knee replacement patients analyzed were admitted in 1992 in 57 acute-care non-federal hospitals. The measurements were of incremental costs or charges expected to be saved as a result of using LMWH prophylaxis instead of warfarin prophylaxis. Prophylaxis using LMWH rather than warfarin reduces the expected total costs (charges) of treatment by $50 ($193), not including the pharmaceutical costs associated with prophylaxis. The cost reduction in favor of LMWH was sensitive to several factors, including blood monitoring costs and DVT/PE complication rates. Where a reduction of one day in hospital stay could be realized from LMWH's early onset of action, the cost (charges) reduction increased to $226 ($624). In conclusion, LMWH has the potential to offer several short- and long-term cost advantages compared with warfarin, mostly due to lower test costs associated with prophylaxis and reduced complication rates.

G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism.

OBJECTIVES: The study was done to determine whether the G20210A mutation in the prothrombin gene increases the risk of recurrent venous thromboembolism (VTE), both alone and in combination with factor V Leiden. BACKGROUND: Several inherited defects of coagulation are associated with increased risk of first VTE, including a recently identified G20210A mutation in the prothrombin gene. However, whether the presence of this mutation confers an increased risk of recurrent venous thromboembolism is controversial. METHODS: A total of 218 men with incident venous thromboembolism were genotyped for the prothrombin mutation and for factor V Leiden and were followed prospectively for recurrent VTE over a follow-up period of 7.3 years. RESULTS: A total of 29 men (13.3%) suffered recurrent VTE. Five of the 14 carriers of the prothrombin mutation developed recurrent VTE (35.7%; incidence rate = 8.70 per 100 person-years), while 24 of 204 individuals who did not carry the prothrombin mutation developed recurrent VTE (11.8%; incidence rate = 1.76 per 100 person-years). Thus, presence of the G20210A mutation was associated with an approximate fivefold increased risk for recurrent VTE (crude relative risk [RR] 4.93; 95% confidence interval [CI] 1.9-12.9; p = 0.001; age-, smoking-, and body mass index-adjusted RR 5.28; 95% CI 2.0-14.0; p = 0.001). In these data, recurrence rates were similar among those with an isolated mutation in the prothrombin gene (18.2%) as compared to those with an isolated factor V Leiden mutation (19.2%). However, all three study participants who carried both mutations (100%) suffered a recurrent event during follow-up. CONCLUSIONS: In a prospective evaluation of 218 men, the presence ofprothrombin mutation was associated with a significantly increased risk of recurrent VTE, particularly among those who co-inherited factor V Leiden.

Epidemiology of pulmonary embolism.

The diagnosis of venous thromboembolism (VTE) has notoriously been challenging because the disease often has no specific clinical presentation, can at times be completely asymptomatic, and can masquerade as other illnesses. To further complicate matters, the rules for coding VTE in the presence of other illnesses changed in 1983 so that among patients who died of VTE and other causes, VTE was omitted from the coding. The International Cooperative Pulmonary Embolism Registry enrolled 2454 consecutive pulmonary embolism (PE) patients from 52 participating hospitals in 7 countries. The aim was to establish the 3-month all-cause mortality rate and to identify factors associated with death. Three-month follow-up was completed in 98% of the patients. The all-cause mortality rate was 11.4% during the first 2 weeks after diagnosis and 17.4% at 3 months. Especially troubling among survivors was the high rate of recurrent VTE after anticoagulation was discontinued. Age is a potent risk factor for the development of VTE. The two most common genetic mutations that predispose to VTE are the factor V Leiden and the prothrombin gene. VTE can be precipitated by oral contraceptives, pregnancy, or hormone replacement therapy.

New onset of venous thromboembolism among hospitalized patients at Brigham and Women's Hospital is caused more often by prophylaxis failure than by withholding treatment.

CONTEXT: Guidelines to prevent venous thromboembolism (VTE) have been widely distributed and generally have been assumed to be effective. Therefore, among hospitalized patients, the development of VTE is thought to occur in the context of omitted prophylaxis. OBJECTIVES: To describe hospitalized patients who develop VTE and to determine whether they received antecedent prophylaxis. DESIGN: Case series. SETTING: Brigham and Women's Hospital. PATIENTS: Three hundred eighty-four patients who developed in-hospital deep venous thrombosis or pulmonary embolism or who developed VTE within 30 days of prior hospital discharge. MAIN OUTCOME MEASURES: The relationship of developing new-onset VTE to the use or omission of antecedent in-hospital prophylaxis. RESULTS: Of the 384 identified patients, 272 had deep venous thrombosis alone, 62 had pulmonary embolism alone, and 50 had deep venous thrombosis and pulmonary embolism. Most were medical service patients; fewer than one fourth were general or orthopedic surgery patients. Overall, 52% had received antecedent VTE prophylaxis. Thirteen deaths (3.4%) were ascribed to pulmonary embolism, and prophylaxis was omitted in only 1 of those 13 patients. CONCLUSIONS: Most deaths from pulmonary embolism among patients hospitalized for other conditions occurred in the setting of failed prophylaxis rather than omitted prophylaxis. High-risk patients, especially medical service patients, warrant intensive VTE prophylaxis and close follow-up to ensure successful outcomes.

The current role of thrombolytic therapy for pulmonary embolism.

Thrombolytic therapy for pulmonary embolism can rapidly reverse right ventricular failure and reduce mortality and morbidity among appropriately selected patients. Individuals being considered for this treatment should be screened for potential major bleeding problems, which, if present, should lead to alternative management with catheter or surgical embolectomy. There is no ideal thrombolytic agent; nor have indications for thrombolysis been precisely defined. Available data indicate that patients with moderate or severe right ventricular dysfunction gain the most from this pharmacologic strategy.

Chest radiographs in acute pulmonary embolism. Results from the International Cooperative Pulmonary Embolism Registry.

OBJECTIVES: To characterize chest radiographic interpretations in a large population of patients who have received a diagnosis of acute pulmonary embolism and to estimate the sensitivity and specificity of chest radiographic abnormalities for right ventricular hypokinesis that has been diagnosed by echocardiography. DESIGN: A prospective observational study at 52 hospitals in seven countries. PATIENTS: A total of 2,454 consecutive patients who had received a diagnosis of acute pulmonary embolism between January 1995 and November 1996. RESULTS: Chest radiographs were available for 2,322 patients (95%). The most common chest radiographic interpretations were cardiac enlargement (27%), normal (24%), pleural effusion (23%), elevated hemidiaphragm (20%), pulmonary artery enlargement (19%), atelectasis (18%), and parenchymal pulmonary infiltrates (17%). The results of chest radiographs were abnormal for 509 of 655 patients (78%) who had undergone a major surgical procedure within 2 months of the diagnosis of pulmonary embolism: normal results for chest radiograph often accompanied pulmonary embolism after genitourinary procedures (37%), orthopedic surgery (29%), or gynecologic surgery (28%), whereas they rarely accompanied pulmonary emboli associated with thoracic procedures (4%). Chest radiographs were interpreted to show cardiac enlargement for 149 of 309 patients with right ventricular hypokinesis that was detected by echocardiography (sensitivity, 0.48) and for 178 of 485 patients without right ventricular hypokinesis (specificity, 0.63). Chest radiographs were interpreted to show pulmonary artery enlargement for 118 of 309 patients with right ventricular hypokinesis (sensitivity, 0.38) and for 117 of 483 patients without right ventricular hypokinesis (specificity, 0.76). CONCLUSIONS: Cardiomegaly is the most common chest radiographic abnormality associated with acute pulmonary embolism. Neither pulmonary artery enlargement nor cardiomegaly appears sensitive or specific for the echocardiographic finding of right ventricular hypokinesis, an important predictor of mortality associated with acute pulmonary embolism.

The approach to massive pulmonary embolism.

Massive pulmonary embolism (PE) is surprisingly common and is not necessarily heralded by dramatic symptoms or signs. The death rate from PE remains high, and the most common cause of mortality is recurrent PE, not cancer. Prevention of recurrent embolism with intensive anticoagulation remains the foundation of therapy. The Food and Drug Administration has approved use of the low molecular weight heparin enoxaparin for inpatient treatment of deep venous thrombosis (DVT) with or without PE as a "bridge'' to warfarin. However, in patients with massive PE, anticoagulation alone often does not suffice to prevent death or disability from chronic pulmonary hypertension. Impending hemodynamic instability due to massive PE and its attendant ominous prognosis can be detected by rapid identification of moderate or severe right ventricular failure (usually easily with transthoracic echocardiography). Successful treatment of overt cardiogenic shock, manifested by systemic arterial hypotension and tachycardia, is far more difficult than implementing a strategy that champions early intervention after the onset of right ventricular failure. Among patients with massive PE, thrombolysis and embolectomy (often performed in the interventional angiography laboratory) are being used with increasing skill and improved outcomes. Intensive pharmacologic therapy and mechanical support devices portend a new era of improved intensive and multidisciplinary management of these gravely ill patients.

Clinically significant venous thromboembolism after gynecologic surgery.

OBJECTIVE: To review the incidence and outcome of clinically significant venous thromboembolism (VTE) following gynecologic surgery in a population receiving provider-specified prophylaxis. STUDY DESIGN: A computerized patient database was used to identify all patients diagnosed with VTE following gynecologic surgery from 1992 to 1997. Medical records were retrospectively reviewed. Clinically significant postoperative VTE was defined as pulmonary embolism or deep venous thrombosis, suggested by symptoms and physical findings, with subsequent confirmation by appropriate imaging study. Patients having VTE at the time of preoperative hospital admission and patients diagnosed with VTE after postoperative day 30 were excluded. RESULTS: Fifty-three patients developed postoperative VTE after > 30,000 gynecologic surgical procedures (incidence, < 1 event per 500 procedures). Forty-eight (91%) patients received some form of prophylaxis. Patients with benign disease, surgical anesthesia less than three hours and no history of prior VTE or factor V Leiden deficiency rarely developed postoperative VTE (incidence, < 1 event in 4,000 procedures). Thirteen (25%) patients had complications from anticoagulation therapy requiring prolonged hospital stay or readmission. CONCLUSION: Clinically significant VTE following gynecologic surgery is rare in the absence of malignancy, prolonged surgical anesthesia or hypercoagulation factors. Complications from anticoagulation therapy are common among gynecologic patients undergoing treatment for VTE.

Venous thromboembolism occurs frequently in patients undergoing brain tumor surgery despite prophylaxis.

Most Neurosurgical Service patients at our hospital receive venous thromboembolism prophylaxis. In 1995-96, the rate of clinically overt venous thromboembolism was 3.7% among patients undergoing neurosurgery. However, rates were much higher when craniotomy was undertaken for brain tumor. Of 497 who underwent craniotomy for primary (429) or metastatic (68) brain tumor, 47 (9.5%) developed clinically overt venous thromboembolism: 7.5% after primary brain tumor resection and 19% after craniotomy for metastatic cancer. The high rate of venous thromboembolism in craniotomy patients with brain tumor warrants study of alternative measures for preventing thrombus, such as prophylaxis with low molecular weight heparin.

Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)

BACKGROUND: Pulmonary embolism (PE) remains poorly understood. Rates of clinical outcomes such as death and recurrence vary widely among trials. We therefore established the International Cooperative Pulmonary Embolism Registry (ICOPER), with the aim of identifying factors associated with death. METHODS: 2454 consecutive eligible patients with acute PE were registered from 52 hospitals in seven countries in Europe and North America. The primary outcome measure was all-cause mortality at 3 months. The prognostic effect of baseline factors on survival was assessed with multivariate analyses. FINDINGS: 2110 (86.0%) patients had PE proven by necropsy, high-probability lung scan, pulmonary angiography, or venous ultrasonography plus high clinical suspicion; ICOPER accepted without independent review diagnoses and interpretation of imaging provided by participating centres; 3-month follow-up was completed in 98.0% of patients. The overall crude mortality rate at 3 months was 17.4% (426 of 2454 deaths, including 52 patients lost to follow-up): 179 of 397 (45.1%) deaths were ascribed to PE and 70 of 397 (17.6%) to cancer, and no information on the cause of death was available for 29 patients. After exclusion of 61 patients in whom PE was first discovered at necropsy, the mortality rate at 3 months was 15.3% (365 of 2393 deaths). On multiple-regression modelling, age over 70 years (hazard ratio 1.6 [95% CI 1.1-2.3]), cancer (2.3 [1.5-3.5]), congestive heart failure (2.4 [1.5-3.7]), chronic obstructive pulmonary disease (1.8 [1.2-2.7]), systolic arterial hypotension (2.9 [1.7-5.0]), tachypnoea (2.0 [1.2-3.2]), and right-ventricular hypokinesis on echocardiography (2.0 [1.3-2.9]) were identified as significant prognostic factors. INTERPRETATION: PE remains an important clinical problem with a high mortality rate. Data from ICOPER provide rates and highlight adverse prognostic categories that will help in planning of future trials of high-risk PE patients.

Late venous thromboembolic disease after radical prostatectomy: effect of risk factors, warfarin and early discharge.

PURPOSE: We determined the incidence of late venous thromboembolic disease after radical prostatectomy, and the influence of risk factors, length of hospital stay and warfarin anticoagulation. MATERIALS AND METHODS: Patients undergoing radical prostatectomy received routine deep vein thrombosis prophylaxis that consisted of intermittent pneumatic compression stockings, early ambulation and warfarin administration during hospitalization with the goal of achieving a prothrombin time international normalized ratio of 1.5 or greater. When patients returned to the hospital for postoperative evaluation, venous duplex ultrasonography of the lower extremities was done. All patients were contacted at 2 months to ensure that they did not suffer a clinical thromboembolic event. RESULTS: One of 158 patients consenting to the study had a symptomatic thromboembolic event for a clinical incidence of 0.6% (95% confidence interval 0.0 to 3.5). Duplex ultrasonography was performed 21.4 +/- 7.8 days postoperatively and 3 of the 106 patients who completed the study had a positive ultrasound for an incidence of 2.8% (95% confidence interval 0.6 to 8.1). None of these patients suffered a symptomatic thromboembolic event. Age, body mass index, length of hospital stay, operative time, estimated blood loss, prostate specific antigen and Gleason score were evaluated for a statistical relationship with thromboembolic events. Only higher body mass index and length of hospitalization approached statistical significance. CONCLUSIONS: Late deep vein thrombosis can occur after radical retropubic prostatectomy. Shorter prophylaxis period, secondary to shorter periods of hospitalization, did not increase the risk of thromboembolic events. The combination of intermittent pneumatic compression stockings and warfarin anticoagulation may be contributing to the relatively low deep vein thrombosis rate in our study compared to previous studies.