Apixaban more effective than enoxaparin in preventing thromboembolism after knee surgery

Apixaban is more convenient and effective an anticoagulant than enoxaparin in preventing venous thromboembolism after knee replacement surgery. In addition, apixaban does not increase the risk of bleeding—a concern with anticoagulants, since this can delay recovery and predispose patients to infections that could damage the prosthesis. These are the conclusions of an Article published in the Lancet today.

Existing prophylactics such as heparins, like enoxaparin, or other drugs such as fondaparinux need regular injections, use of warfarin has various disadvantages in routine practice, and mechanical methods are cumbersome.

Michael Rud Lassen, Department of Orthopaedics, Horsholm Hospital, University of Copenhagen, Denmark, and colleagues undertook a randomised controlled phase 3 trial to see whether apixaban would be better than enoxaparin in both keeping thromboembolism and bleeding to a minimum. The patients either received 2.5 mg of apixaban twice daily or 40 mg enoxaparin once daily. The primary outcome was a composite of deep vein thrombosis, non-fatal pulmonary embolism, and death from any cause.

147 (15% of 976) patients on apixaban and 243 (24% of 997) on enoxaparin had a primary outcome event—a statistically significant difference. There was no significant difference between the groups in the bleeding during treatment.

The authors say: "2•5 mg apixaban twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding."

They conclude: "These favourable results might help surgeons to resolve their clinical dilemma when considering anticoagulant prophylaxis for total knee replacement. Bleeding can delay recovery and can predispose to infections that endanger the prosthesis. The small but occasionally important increase in surgical bleeding that is attributed to enoxaparin can contribute to underuse of effective prophylaxis."

In an accompanying Comment, Dr Jawed Fareed, Department of Pathology, Loyola University Medical Center, Maywood, IL, USA, and Dr Russell Hull, University of Calgary, Calgary, Canada say: "we are potentially a step closer to the unmet need of oral antithrombotic therapy without need for monitoring."

They conclude: "The ideal prophylactic drug would reduce the frequency of postoperative venous thromboembolism without causing bleeding and other complications in patients postoperatively. An ideal drug does not yet exist. The balance is fairly simple: a stronger anticoagulant effect is associated with fewer thrombotic events, but with a cost of increased occurrence of bleeding."

Dr Michael Rud Lassen, Department of Orthopaedics, Horsholm Hospital, University of Copenhage, Denmark. T) +45 21 77 88 60 E) mirula@noh.regionh.dk

Dr Jawed Fareed, Department of Pathology, Loyola University Medical Center, Maywood, IL, USA. E) jfareed@lumc.edu

For full Article and Comment, see: http://press.thelancet.com/advance.pdf

Vaginal brachytherapy (VBT), where radiotherapy is given internally, is as effective as external beam radiotherapy (EBRT) in preventing local disease recurrence with similar rates of survival, but with significantly less toxicity and better quality of life, in patients with high-intermediate risk* endometrial cancer. Wherever possible, VBT should replace EBRT and become the standard treatment for all patients with high-intermediate risk endometrial cancer after surgery, concludes an Article published in this week's edition of the Lancet.

Endometrial cancer is the most common gynaecological cancer in postmenopausal women in developed countries and, because of an aging population, incidence of the disease is increasing. About 80% of patients are diagnosed with stage 1 disease in which the initial treatment is usually surgery (removal of the uterus and ovaries). Radiotherapy (VBT or EBRT) is given after surgery to patients at high-intermediate risk as it lowers the likelihood of local disease recurrence from about 20% to 5%. However, the best adjuvant radiotherapy treatment option remains unclear and practices vary widely.

In 2002, the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC-2) trial commenced to examine whether VBT is as effective as EBRT at preventing vaginal recurrence (the most frequent site of recurrence in patients with high-intermediate risk endometrial cancer), whilst monitoring occurrence of possible side effects and resulting quality of life.

427 patients were randomly assigned to EBRT (46 Gy in 23 fractions) or VBT (21 Gy high-dose rate in three fractions or 30 Gy low-dose rate). Quality of life was assessed using self-reported questionnaires completed at regular intervals after treatment for up to 5 years. Preliminary results showed that in the first 2 years after treatment patients who received EBRT experienced significantly more gastrointestinal toxic effects, especially diarrhoea, more often resulting in limitations to their daily activities and decreased social functioning.

In today's study, the PORTEC team report the main trial results on efficacy, side-effects, and patient-reported quality of life, to establish the best adjuvant treatment option for patients with high-intermediate risk endometrial cancer.

Findings showed that at median follow-up of 45 months, very few vaginal recurrences occurred in either radiotherapy group (3 for VBT vs 4 for EBRT), showing VBT to be very effective in ensuring local disease control. Estimated 5-year vaginal recurrence rates were 1.8% after VBT and 1.6% after EBRT.

Additionally, there were no significant differences in 5-year locoregional (vaginal or pelvic or both) recurrence, and rates of overall (84.8% for VBT vs 79.6% for EBRT) and disease-free survival (82.7% vs 78.1% for EBRT) were similar.

Importantly, patients in the EBRT group experienced significantly higher rates of mild to moderate gastrointestinal adverse events than those in the VBT group at completion of radiotherapy (53.8% vs 12.6%). While the occurrence of adverse events did decrease in the EBRT group over time, rates remained significantly higher compared to VBT.

The authors say: "PORTEC-2 shows that patients at high-intermediate risk, about 30% of all patients with endometrial cancer, can be safely treated with vaginal brachytherapy alone, with fewer side-effects and improved quality of life. EBRT will thus be used only for the 15% of patients with high-risk or advanced disease."

They conclude: "VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk."

In an accompanying Comment, Henry Kitchener from the University of Manchester Academic Health Science Centre, Manchester, UK, and Melanie Powell from the Barts and London NHS Trust, London, UK agree with the recommendations of the trial authors and say that VBT should become the standard of care in these patients. They point out that: "VBT is not as widely available as is EBRT so patients might need to travel further for treatment, but VBT needs fewer treatments and has a better toxicity profile than does EBRT, and is associated with improved quality of life for a similar outcome."

Contact:

Dr Remi Nout, Leiden University Medical Centre, Leiden, Netherlands. T) +31 (0) 71 5266873 or +31 (0) 71 5269111, pager 8333. E) r.a.nout@lumc.nl

Professor Henry Kitchener, University of Manchester Academic Health Science Centre, Manchester, UK T) +44 (0)161 276 6461 E) henry.kitchener@manchester.ac.uk

For full Article and Comment, see: http://press.thelancet.com/portec.pdf

Notes to Editors:

*Patients with high-intermediate risk are defined as having endometrioid type carcinoma with two of three major risk factors for recurrence—invasion in the outer half of the myometrium, grade 3 histology, or age greater than 60 years.

THIS WEEK'S EDITORIALS: INTERNATIONAL WOMEN'S DAY, ANTIPHOSPHOLIPID SYNDROME, RESPONSIBLE INTERNET USE

For full Editorials, see: http://press.thelancet.com/editorials03032010.pdf