Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

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.

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - the SAVE-HIP3 study.

There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis.

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

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.

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

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.

Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme.

Post-operative complications after total hip or knee replacement can delay recovery, prolong hospitalisation, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death. In this analysis of pooled data from four large, randomised, phase III clinical trials that compared the oral, direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement (n = 12,729), the incidence of complications, including bleeding and adverse events related to surgery (such as wound infection, wound dehiscence and haemarthrosis) are reported. Interventions and procedures relating to surgery are also compared between the groups. Bleeding events, including excessive wound haematoma and surgical-site bleeding, occurred at similar rates in the rivaroxaban and enoxaparin groups. Over the total study duration, adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement (2.26% vs. 2.69%, respectively) and total hip replacement (1.48% vs. 1.65%, respectively). Blood loss, wound drainage and transfusion requirements were also similar between the two groups. This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin.

Solitary lymphangioleiomyoma of pancreas mimicking pancreatic pseudocyst--a case report.

INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of morphologically distinguishable smooth muscle cells in the lymphatics and lymph nodes of the pulmonary parenchyma in most cases. Extrapulmonary LAM is a rare condition and is found to occur concurrently, before or after pulmonary LAM, and show strong association with tuberous sclerosis. DISCUSSION: The literature regarding extrapulmonary LAM without associated pulmonary LAM is limited due to the extreme rarity of the cases. We hereby describe clinical, pathological and radiological features of primary pancreatic LAM presenting clinicoradiologically as pseudocyst of pancreas in a 43-year-old lady. CONCLUSION: The present case is unique as LAM in pancreas without associated pulmonary LAM has never been reported in the literature before.

Small cell carcinoma of the renal pelvis: a case report and review of the literature.

Extrapulmonary small cell carcinoma occurs in nearly all organs except the central nervous system and the liver. We are presenting a case of renal small cell carcinoma (SCC) with two unique characters. A 75-year-old patient was evaluated for back pain with no other complaints. Magnetic Resonance (MR) imaging of the abdomen revealed homogeneous tumor in the left renal pelvis extending beyond the kidney. Metastatic workup was negative. A left nephroureterectomy was performed. Histopathology and immunohistochemistry revealed a small cell carcinoma of the renal pelvis. The patient declined adjuvant therapy and died 2 months after surgery due to unrelated causes. After comprehensive worldwide literature search, we found 13 cases of SCC of the renal pelvis, including the current case. The mean age was 61.6 years (37-83), with a M : F ratio of 1 : 1.8. The average duration of symptoms was 71.4 days (21-168). Gross hematuria was the most common symptom (69.2%) followed by pain (61.5%). Adjuvant chemotherapy was provided to 4 patients (30.7%), and neoadjuvant to 1 patient. The median survival of patients who did and did not receive chemotherapy was 5.5 months (3-8) and 6 months (2-31), respectively, P < .50. In conclusion, renal SCC (both parenchymal and pelvic SCC) is a rapidly fatal disease with a median survival of ≤8 months.

Antithrombotic therapy and survival in patients with malignant disease.

A broad range of studies suggest a two-way relationship between cancer and venous thromboembolism (VTE). Patients with cancer have consistently been shown to be at elevated risk for VTE; this risk is partly driven by an intrinsic hypercoagulable state elicited by the tumour itself. Conversely, thromboembolic events in patients without obvious risk factors are often the first clinical manifestation of an undiagnosed malignancy. The relationship between VTE and cancer is further supported by a number of trials and meta-analyses which, when taken together, strongly suggest that antithrombotic therapy can extend survival in patients with cancer by a mechanism that extends beyond its effect in preventing VTE. Moreover, accumulating evidence from in vitro and in vivo studies has shown that tumour growth, invasion, and metastasis are governed, in part, by elements of the coagulation system. On 22 May 2009, a group of health-care providers based in the United Kingdom met in London, England, to examine recent advances in cancer-associated thrombosis and its implications for UK clinical practice. As part of the discussion, attendees evaluated evidence for and against an effect of antithrombotic therapy on survival in cancer. This paper includes a summary of the data presented at the meeting and explores potential mechanisms by which antithrombotic agents might exert antitumour effects. The summary is followed by a consensus statement developed by the group.

Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement.

A once-daily dose of rivaroxaban 10 mg, an oral, direct Factor Xa inhibitor, was compared with enoxaparin 40 mg subcutaneously once daily for prevention of venous thromboembolism in three studies of patients undergoing elective hip and knee replacement (RECORD programme). A pooled analysis of data from these studies (n = 9581) showed that rivaroxaban was more effective than enoxaparin in reducing the incidence of the composite of symptomatic venous thromboembolism and all-cause mortality at two weeks (0.4% vs 0.8%, respectively, odds ratio 0.44; 95% confidence interval 0.23 to 0.79; p = 0.005), and at the end of the planned medication period (0.5% vs 1.3%, respectively; odds ratio 0.38; 95% confidence interval 0.22 to 0.62; p < 0.001). The rate of major bleeding was similar at two weeks (0.2% for both) and at the end of the planned medication period (0.3% vs 0.2%). Rivaroxaban started six to eight hours after surgery was more effective than enoxaparin started the previous evening in preventing symptomatic venous thromboembolism and all-cause mortality, without increasing major bleeding.

Antithrombotic therapy and survival in cancer patients.

Venous thromboembolism is a common complication in patients with malignant disease. The development of symptomatic thromboembolism is associated with a poor prognosis for patients with cancer. Retrospective analysis of studies comparing unfractionated heparin with low-molecular-weight heparin (LMWH) for the initial treatment of deep vein thrombosis indicated improved survival for cancer patients receiving LMWH therapy. Prospective studies exposing cancer patients to LMWH therapy, in the absence of established thrombosis, suggest that survival may be prolonged in these patients after LMWH exposure. Ongoing studies, with careful attention to distribution of prognostic variables for cancer outcome, will help to answer the question regarding whether LMWH may indeed be used for this indication.

A randomized, double-blind, placebo-controlled study comparing the efficacy and safety of paracetamol, serratiopeptidase, ibuprofen and betamethasone using the dental impaction pain model.

Assessment of postoperative sequelae following the removal of an impacted third molar has been used in clinical pharmacology to evaluate the relative efficacy of various analgesic, anti-inflammatory drugs. This study included 150 patients with impacted lower third molars. They were randomly sorted to receive ibuprofen, paracetamol, betamethasone, serratiopeptidase or placebo. Evaluation of efficacy was made using tape measurement (for swelling), visual analogue scale (for pain evaluation), mouth opening ability and oral temperature. The effect of treatment on hematological parameters, bleeding, wound healing and requirement for rescue medication was also studied. Peak pain scores were observed approximately 5-6 hours after the operation. Betamethasone showed significant analgesic activity from day 1. Ibuprofen and betamethasone were significantly more effective than placebo in reducing swelling. Trismus was least with betamethasone. A significant rise in temperature on the operated side occurred only on day 1 in all the groups. Serratiopeptidase did not showed significant analgesic and anti-inflammatory action. Mild-to-moderate adverse effects were reported.

Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use.

AIM: Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events. METHODS: First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compared drugs and technical procedure. RESULTS: The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated. CONCLUSION: Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.

The role of radiotherapy in treating small early invasive breast cancer.

AIM: The aim of the study was to identify if radiotherapy can be safely avoided in a selected subgroup of largely screening detected small invasive breast cancer. METHODS: One hundred and eighty-eight patients with node negative invasive early breast cancer < or =1cm (< or =T1b) treated in our centre between 1990 and 2004 were retrospectively followed for local, regional and distant recurrences. Treatment involved adequate local excision by breast conserving surgery (BCS). Axillary staging was performed by a four node axillary sampling until 2000, following which sentinel lymph node sampling was employed. All sections were assessed histologically by haematoxylin and eosin stained sections. The inked margins were reported as being involved, close and clear. Radiotherapy (RT) was employed only if the resected margins were inadequate, and in those with involved axillary nodes who refused further completion axillary clearance. RESULTS: Ninety-four patients (Group A) had BCS alone and 79 patients (Group B) had both BCS and RT. There was no ipsilateral breast tumour recurrence (IBTR) in 88 patients in Group A, corresponding to an actuarial freedom from IBTR of 96%, 91% and 88.1% at 5 years, 8 years and 9 years. In Group B, there was no IBTR in 75 patients corresponding to an actuarial freedom from IBTR of 97%, 94.9% and 90.6% at 5 years, 8 years and 10 years. CONCLUSION: Our experience over 14 years has shown that it is possible to safely avoid radiotherapy in a selected subgroup of small invasive breast cancer.

Ultrasound screening for asymptomatic deep vein thrombosis after major orthopaedic surgery: the VENUS study.

BACKGROUND: Venography is currently used to assess the incidence of deep vein thrombosis (DVT) in dose-finding and confirmatory trials of new antithrombotic agents. Centrally adjudicated, complete compression ultrasound (CCUS) could be a non-invasive alternative to venography. OBJECTIVES: A substudy of two, similarly designed, phase IIb trials of a novel, oral anticoagulant for the prevention of venous thromboembolism after elective hip or knee arthroplasty was undertaken to validate CCUS against venography. PATIENTS/METHODS: Patients received study drugs until mandatory, bilateral venography was performed 7 +/- 2 days after surgery. CCUS was performed within 24 h after venography by sonographers blinded to the venography result. Sonographers were trained and certified for the standardized examination and documentation procedure. Venograms and sonograms were adjudicated centrally at different sites by two independent readers; discrepancies between readers were resolved by consensus. RESULTS: A total of 1104 matching pairs of evaluable venograms and sonograms were obtained from the participants of the two trials (n = 1435): 19% of venograms and 20% of sonograms were not evaluable. The observed frequency of any DVT was 18.9% with venography and 11.5% with CCUS. Sensitivity of CCUS compared with venography was 31.1% for any DVT (95% confidence interval 23.4, 38.9), 21.0% (2.7, 39.4) for proximal DVT, and 30.8% (23.1, 38.6) for distal DVT. The figures for specificity were 93.0% (91.0, 95.1), 98.7% (98.0, 99.5), and 93.3% (91.5, 95.3), respectively. CONCLUSIONS: Based on these results, centrally adjudicated CCUS will be unable to replace venography for DVT screening early after major orthopaedic surgery in studies evaluating anticoagulant drugs.

Management of venous thromboembolism.

INTRODUCTION: Venous Thromboembolism is an important healthcare problem the world over, resulting in significant morbidity, mortality and resource expenditure. The rationale for use of thromboprophylaxis is based on solid principles and scientific evidence. Indian perspective on this topic is lacking due to the non-availability of published Indian data. This document reviews the available International and Indian data and discusses the relevance of recommendations for prevention and management of Venous Thromboembolism (VTE) in the Indian context. MATERIALS AND METHODS: Meetings of various specialists from different Indian hospitals in the field of Gastrointestinal Surgery, General and Vascular Surgery, Hematology, Intensive Care, Obstetrics and Gynecology, Oncology and Orthopedics were held in the months of August 2005 to January 2006. The guidelines published by American College of Chest Physicians (ACCP), the International Union of Angiology (IUA), and the Royal College of Obstetricians and Gynecologists (RCOG), were discussed during these meetings. The relevance of these guidelines and the practical implications of following these in a developing country like India were also discussed. Any published data from India was collected from data base searches and the results, along with personal experiences of the participating specialists were discussed. The experiences and impressions of the experts during these meetings have been included in this document. Data from recent sources (International Union of Angiology and the National Comprehensive Cancer Network (NCCN) Practice guidelines in Oncology on Venous thromboembolic disease) was subsequently also included in this document. RESULTS: The suggestions formulated in this document are practical, and would intend to serve as a useful practical reference. CONCLUSIONS: A number of unanswered questions remain in the field of thromboprophylaxis, and carefully designed research protocols may help answer some of these. Implementation of the suggestions outlined in the document remains to be studied in the Indian context.