Michael B. Streiff

International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer

Summary.  Background: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. Objectives: To establish a common international consensus addressing practical, clinically relevant questions in this setting. Methods: An international consensus working group of experts was set up to develop guidelines according to an evidence‐based medicine approach, using the GRADE system. Results: For the initial treatment of established VTE: low‐molecular‐weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case‐by‐case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long‐term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3–6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit‐risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12–2 h preoperatively and continued for at least 7–10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l‐asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low‐dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl < 30 mL min−1), thrombocytopenia and pregnancy. Guidances are provided in these contexts. Conclusions: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.

Management of Venous Thromboembolism: A Systematic Review for a Practice Guideline

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism, is a prevalent disease treated by internists. The incidence of VTE is about 7 per 10000 person-years among community residents (1, 2). The condition recurs in about 20% of patients after 5 years, but the rate varies depending on the presence of risk factors (3, 4). A community-wide study from the 1980s reported an incidence rate of pulmonary embolism, with or without DVT, of 2.3 per 10000 (5). Pulmonary embolism limits the short- and long-term survival of patients with VTE (6). Postthrombotic syndrome, another prevalent complication of DVT, may result in life-long morbidity with limb pain and edema (4). Treatment of VTE, with anticoagulants and thrombolytic therapies, is associated with its own risks. Given the prevalence of this condition and its associated morbidity, we reviewed the evidence on optimal treatment of VTE. We sought to summarize the evidence to inform the guidelines developed by the American Academy of Family Physicians and the American College of Physicians for management of patients with VTE. The foundation of this background paper was a previous systematic review of diagnosis and management of VTE (7). For this paper, we addressed the following questions: 1) Is heparin or low-molecular-weight heparin (LMWH) safer and more efficacious for initial treatment of VTE? 2) Is outpatient treatment of VTE safe and effective when compared with inpatient treatment? 3) Is LMWH cost-effective compared with heparin? 4) Does catheter-directed thrombolysis reduce VTE recurrences and the incidence of postthrombotic syndrome? 5) Does use of compression stockings reduce the incidence of postthrombotic syndrome? 6) Do vena cava filters alter the incidence of pulmonary embolism and recurrent DVT? 7) What is the optimal duration of therapy with vitamin K antagonists for VTE? 8) Does evidence support use of LMWH instead of vitamin K antagonists? 9) What is the best therapy for pregnant women with VTE? Methods The methods used in our systematic review are completely described in a detailed evidence report (7). The methods specific to this article are briefly described in the following section. Data Sources To identify relevant articles, we searched literature-indexing systems, including MEDLINE, MICROMEDEX, the Cochrane Controlled Trials Register, and the Cochrane Database of Systematic Reviews, beginning in the 1950s. We also examined reference lists from material identified through the electronic searching and from discussion with experts, and we reviewed recent tables of contents of the pertinent journals. For our previous report, we searched for citations through March 2002. For the current review, we extended the search through June 2006. Data Selection Our criteria for article inclusion are listed in Appendix 1. Two team members independently reviewed the titles and abstracts and excluded those that did not meet the eligibility criteria. For primary literature, the article must have been in English, addressed one of the chosen questions, not involved prevention only, included original human data, and not have been a single-patient case report. For our review of systematic reviews, we used these criteria but also stipulated that the article have included a systematic review, meta-analysis, or cost-effectiveness analysis. Data published only in abstract form were excluded. Each question had additional eligibility criteria. If both reviewers agreed about eligibility, we reviewed the article. In our previous review, we evaluated 64 systematic reviews and 148 primary studies. Of these, 16 systematic reviews and 32 primary studies were relevant to our questions about management of VTE. In our additional searching, we identified another 3 systematic reviews and 13 primary studies on the questions that were in the previous review. We also reviewed 515 additional abstracts to identify 46 primary studies on 5 additional questions covered in this review. Seven studies, previously included for question 7 above, were eliminated; they were published before 1995 and were inconsistent in their use of objective tests for diagnosing VTE. Data Extraction and Quality Assessment A single reviewer abstracted data, and a co-investigator did a secondary review to verify accuracy. We summarized data in evidence tables and assessed the quality of the article by using validated instruments, where appropriate (8). Two authors graded evidence according to the Strength of Recommendation Taxonomy (SORT) developed by a consortium of editors of U.S. family medicine and primary care journals (9). As shown in Table 1, level 1 indicates good-quality patient-oriented evidence, level 2 indicates limited-quality patient-oriented evidence, and level 3 indicates when there is other evidence. Table 1. Assessing Quality of Evidence* Data Synthesis and Analysis We pooled risk ratios across studies about duration of oral anticoagulation and generated CIs around the risk ratios with a random-effects model using the method of DerSimonian and Laird; the estimate of heterogeneity was taken from the Mantel-Haenszel model (Stata 9.0, StataCorp., College Station, Texas). The I2 statistic was calculated as 100%(Qdegrees of freedom)/Q, where Q is the measure of heterogeneity (10). Because the I2 statistic suggested heterogeneity between trials, we do not report pooled results. Role of the Funding Sources The initial systematic review was funded through a contract with the Agency for Healthcare Research and Quality. Members of the American College of Physicians/American Academy of Family Physicians guidelines committee for management of VTE reviewed drafts of this manuscript. Data Synthesis Is Heparin or LMWH Safer and More Efficacious for Initial Treatment of VTE? Numerous trials have compared the safety and efficacy of LWMHs to those of unfractionated heparin in the treatment of VTE. We report on 17 systematic reviews of these trials, published between 1994 and 2003, which reviewed rates of recurrent VTE, major bleeding, or death (1127). Five included only trials of patients with an isolated DVT, 1 review focused on patients with pulmonary embolism with or without concomitant DVT (23), and 1 evaluated the adequacy of dosing of unfractionated heparin (24). Thirteen LMWHs were compared with unfractionated heparin, almost always given intravenously. The LMWHs most often included were enoxaparin (13 reviews), dalteparin (12 reviews), nadroparin (11 reviews), tinzaparin (10 reviews), reviparin (9 reviews), and CY222 (8 reviews). The quality of the systematic reviews was generally good, although only 5 evaluated the quality of trials (14, 17, 23, 26, 28). Description of the search strategies and methods of combining results were weaker in the earlier reviews. Five reviews were descriptive and did not pool results (11, 18, 19, 22, 24). As expected, many of the same articles were included in multiple reviews. The reviews fell into 3 clusters depending on which trials they included. Table 2 summarizes the pooled trial results by these clusters. The cluster containing the most recent trials, cluster C, has odds ratios closer to 1.0 than the cluster containing only the earliest trials. Appendix Table 1 describes the individual trials within each review). Table 2. Systematic Reviews Comparing Low-Molecular-Weight Heparin with Unfractionated Heparin (n= 10)* Appendix Table 1. Individual Studies Included in Systematic Reviews The 5 descriptive reviews had discordant results (11, 18, 19, 22, 24). Among the 11 reviews that pooled trial results (with many trials in common), none showed heparin to be superior to LMWH in preventing recurrent DVT. In addition, patients treated with LMWH had fewer episodes of major bleeding than those treated with unfractionated heparin. All but 1 of 10 reviews showed that LMWH significantly reduced mortality during the 3 to 6 months of follow-up compared with unfractionated heparin (23). Only 4 reviews reported summary results separately for patients with pulmonary embolism; these reviews concluded that LMWH was as effective as unfractionated heparin in this population (16, 18, 23, 29). In summary, evidence is ample that LMWH is superior to unfractionated heparin for the treatment of DVT, particularly for reducing mortality and the risk for major bleeding during initial therapy. The magnitude of benefit from LMWH, while significant in many of these reviews, appears to be lower than was estimated in the earliest reviews. Additional trials are needed to examine the efficacy of LMWH for the treatment of pulmonary embolism, but reviews of existing trials indicate that LMWH is at least as effective as unfractionated heparin for these patients as well. This is level 1 evidence. Is Outpatient Treatment of VTE Safe and Effective When Compared with Inpatient Treatment? Thirteen studies compared the outcomes of patients with VTE treated with LMWH administered at home with outcomes of those treated with unfractionated heparin in the hospital (3042). Four of these were randomized trials (3032, 42); 9 were cohort studies. An additional 5 studies, including 2 randomized trials (43, 44), compared outcomes and costs for patients receiving LMWH at home with those for patients receiving LWMH in the hospital (4347). The studies used subcutaneous enoxaparin, nadroparin, tinzaparin, or dalteparin at varying dosages, and then an oral anticoagulant during follow-up. At least 8 studies allowed a brief inpatient admission for stabilization of patients randomly assigned to the outpatient group. Three studies permitted enrollment of patients with concomitant pulmonary embolism (38, 41, 47), while 1 prospective cohort study required stable patients with pulmonary embolism (45). The remaining studies excluded these patients. Inclusion criteria were restrictiveinvestigators screened far more patients than they enrolled. Most studies excluded patients with previous VTE, thrombophilic c

Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure

BACKGROUND: FV inhibitors are a largely preventable iatrogenic coagulopathy in which the frequency is increasing in clinical practice.

International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer

Summary.  Background: Although long‐term indwelling central venous catheters (CVCs) may lead to pulmonary embolism (PE) and loss of the CVC, there is lack of consensus on management of CVC‐related thrombosis (CRT) in cancer patients and heterogeneity in clinical practices worldwide. Objectives: To establish common international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer patients. Methods: An international working group of experts was set up to develop GCPG according to an evidence‐based medicine approach, using the GRADE system. Results: For the treatment of established CRT in cancer patients, we found no prospective randomized studies, two non‐randomized prospective studies and one retrospective study examining the efficacy and safety of low‐molecular‐weight heparin (LMWH) plus vitamin K antagonists (VKAs). One retrospective study evaluated the benefit of CVC removal and two small retrospective studies were on thrombolytic drugs. For the treatment of symptomatic CRT, anticoagulant treatment (AC) is recommended for a minimum of 3 months; in this setting, LMWHs are suggested. VKAs can also be used, in the absence of direct comparisons of these two types of anticoagulants in this setting [Guidance]. The CVC can be kept in place if it is functional, well‐positioned and non‐infected and there is good resolution under close surveillance; whether the CVC is kept or removed, no standard approach in terms of AC duration has been established [Guidance]. For the prophylaxis of CRT in cancer patients, we found six randomized studies investigating the efficacy and safety of VKA vs. placebo or no treatment, one on the efficacy and safety of unfractionnated heparin, six on the value of LMWH, one double‐blind randomized and one non randomized study on thrombolytic drugs and six meta‐analyses of AC and CVC thromboprophylaxis. Type of catheter (open‐ended like the Hickman® catheter vs. closed‐ended catheter with a valve like the Groshong® catheter), its position (above, below or at the junction of the superior vena cava and the right atrium) and method of placement may influence the onset of CRT on the basis of six retrospective trials, four prospective non‐randomized trials, three randomized trials and one meta‐analysis. In light of these data: use of AC for routine prophylaxis of CRT is not recommended [1A]; a CVC should be inserted on the right side, in the jugular vein, and distal extremity of the CVC should be located at the junction of the superior vena cava and the right atrium [1A]. Conclusion: Dissemination and implementation of these international GCPG for the prevention and treatment of CRT in cancer patients at each national level is a major public health priority, needing worldwide collaboration.

Venous Thromboembolism Prophylaxis and Treatment in Cancer: A Consensus Statement of Major Guidelines Panels and Call to Action

PURPOSE Venous thromboembolism (VTE) is an increasingly frequent complication of cancer and its treatments, and is associated with worsened mortality and morbidity in patients with cancer. DESIGN The Italian Association of Medical Oncology, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, the French National Federation of the League of Centers Against Cancer, and the European Society of Medical Oncology have recently published guidelines regarding VTE in patients with cancer. This review, authored by a working group of members from these panels, focuses on the methodology and areas of consensus and disagreement in the various clinical guidelines as well as directions for future research. RESULTS There is broad consensus regarding the importance of thromboprophylaxis in hospitalized patients with cancer, including prolonged prophylaxis in high-risk surgical patients. Prophylaxis is not currently recommended for ambulatory patients with cancer (with exceptions) or for central venous catheters. All of the panels agree that low molecular weight heparins are preferred for the long-term treatment of VTE in cancer. Areas that warrant further research include the benefit of prophylaxis in the ambulatory setting, the risk/benefit ratio of prophylaxis for hospitalized patients with cancer, an understanding of incidental VTE, and the impact of anticoagulation on survival. CONCLUSION We call for a sustained research effort to investigate the clinical issues identified here to reduce the burden of VTE and its consequences in patients with cancer.

Guidelines on use of vena cava filters

Summary of key recommendations • VC filters are indicated to prevent pulmonary embolus(PE) in patients with venous thromboembolism (VTE)who have a contraindication to anticoagulation (grade B,level III).• Anticoagulation should be considered in patients with aVC filter when a temporary contraindication to antico-agulant therapy is no longer present. Insufficient dataexists to support a recommendation that all filter recip-ients should be treated with indefinite anticoagulationregardless of their risk of recurrent thrombosis (grade C,level IV). The decision as to whether or not to introduceanticoagulant therapy should be based on the perceivedunderlying thrombotic risk of the condition and thelikelihood of anticoagulant therapy-related bleeding.• VC filters are not indicated in unselected patients withVTE who will receive conventional anticoagulant therapy(grade A, level Ib).• VC filter insertion may be considered in selected patientswith PE despite therapeutic anticoagulation. Alternativetreatment options, such as long-term high-intensity oralanticoagulant therapy [international normalised ratio(INR) target 3AE5] or low molecular weight heparin(LMWH), should be considered prior to VC filterplacement, particularly in patients with thrombophilicdisorders (e.g. antiphospholipid syndrome) or cancer(grade C, level IV).• VC filter insertion may be considered in pregnantpatients who have contraindications to anticoagulationor develop extensive VTE shortly before delivery (within2 weeks). Retrievable filters should be considered (gradeC, level IV).• Free-floating thrombus is not an indication for insertionof a VC filter (grade B, level III).• Thrombolysis is not an indication for filter insertion. If afilter is used a retrievable filter should be used if available(grade C, level IV).• VC filters should be considered in any pre-operativepatient with recent VTE (within 1 month) in whomanticoagulation must be interrupted. Retrievable VCfilters should be considered in this situation where atemporary contraindication to anticoagulation exists(grade C, level IV).• No particular filter appears superior to others. Removablefilters should be used, if available, for patients with ashort-term contraindication to anticoagulant therapy(e.g. approximately 2 weeks) (grade C, level IV).

Management of Venous Thromboembolism in Patients With Primary and Metastatic Brain Tumors

Venous thromboembolism occurs commonly throughout the clinical course of patients with brain tumors. A number of hemostatic and clinical factors contribute to this hypercoagulable state. Concern over the possibility of intracranial bleeding has limited the use of anticoagulation in this population. However, mechanical approaches such as vena cava filters have high complication and treatment failure rates in patients with intracranial malignancies. In addition, the available data suggest that anticoagulation can be used safely and effectively in most of these patients. Patients with thrombocytopenia, recent neurosurgery, and tumor types prone to bleeding require special consideration. When intracranial hemorrhage does occur, it is often due to overanticoagulation, requiring prompt anticoagulation reversal and neurosurgical consultation.

Adjunctive percutaneous mechanical thrombectomy for lower-extremity deep vein thrombosis: clinical and economic outcomes.

PURPOSE To assess the clinical and economic benefits of catheter-directed thrombolysis (CDT) alone versus CDT with rheolytic percutaneous mechanical thrombectomy (PMT) for lower-extremity deep vein thrombosis (DVT). MATERIALS AND METHODS Consecutive patients with acute iliofemoral DVT treated with CDT with urokinase between 1997 and 2003 were identified. Demographic characteristics and clinical and economic outcomes were compared between patients treated with CDT alone versus CDT plus PMT. RESULTS Twenty-six limbs in 23 patients received CDT with urokinase, whereas 19 limbs in 14 patients were treated with CDT plus PMT. Mean treatment duration for CDT was 56.5 +/- 27.4 hours, compared with 30.3 +/- 17.8 hours for CDT plus PMT (P = .001). Mean urokinase dose for CDT was 6.70 +/- 5.9 million U compared with 2.95 +/- 1.82 million U for CDT plus PMT (P = .011). Urokinase CDT achieved complete clot lysis in 80.7% of limbs (n = 21) compared with 84.2% of limbs (n = 16) treated with CDT plus PMT (P = .764). The incidences of major bleeding (CDT, 7.7%; CDT plus PMT, 5.3%; P = .749) and pulmonary embolism (CDT, 3.8%; CDT plus PMT, 5.3%; P = .818) were similar. The mean urokinase and PMT device cost for CDT alone was

Lessons from the Johns Hopkins Multi-Disciplinary Venous Thromboembolism (VTE) Prevention Collaborative

10,127 compared with

Improved Prophylaxis and Decreased Rates of Preventable Harm With the Use of a Mandatory Computerized Clinical Decision Support Tool for Prophylaxis for Venous Thromboembolism in Trauma

5,128 for CDT plus PMT (P = .026). CONCLUSIONS Percutaneous CDT with rheolytic PMT is as effective as CDT alone for acute iliofemoral DVT but requires significantly shorter treatment and lower lytic agent dose, resulting in lower costs. Randomized studies to confirm the benefits of pharmacomechanical thrombolysis in the treatment of DVT are warranted.