Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of dabigatran etexilate (DBG) for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip and knee surgery based upon a review of the manufacturer's submission to the NICE as part of the single technology appraisal (STA) process. The submission's evidence came from three reasonable-quality trials comparing DBG with enoxaparin, and a comparison of DBG with fondaparinux based on the relative efficacy and safety as derived from a mixed treatment comparison (MTC) meta-analysis. DBG (220 mg and 150 mg once daily) is not inferior to enoxaparin (40 mg once daily and 30 mg twice daily) in terms of major VTE or VTE-related events (secondary outcome). Meta-analysis shows that 220 mg DBG is not inferior to enoxaparin (40 mg once daily or 30 mg twice daily) in reducing total VTE and all-cause mortality (primary outcome) in total hip or knee replacement, whereas there is uncertainty around the clinical effectiveness of 150 mg DBG for this outcome. In the MTC analysis DBG compared favourably with the other interventions, with the exception of extended enoxaparin and fondaparinux. The adverse event profile was not significantly different in those receiving DBG and those receiving enoxaparin. The submitted two-phase economic model compares DBG with enoxaparin and fondaparinux in total hip and knee replacement. The model structure is appropriate and the model assumptions are reasonable. The health states, costs, utilities and recurrence rates used are considered to be appropriate for the required analysis. The model estimated that at the licensed dose of 220 mg once daily DBG dominates enoxaparin in both total hip replacement and total knee replacement and that at the lower dose of 150 mg once daily DBG dominates enoxaparin in total hip replacement and enoxaparin dominates DBG in total knee replacement. DBG is less cost-effective than fondaparinux in total hip replacement at both doses; the cost per quality-adjusted life-year of fondaparinux versus DBG is 11,111 pounds and 6857 pounds for the higher and lower doses of DBG respectively. In total knee replacement, both DBG doses are dominated by fondaparinux. For DBG versus all comparators in all cases the cost-effectiveness results are based on small incremental cost and health benefits. Weaknesses of the submitted evidence include that methods used for screening studies, data extraction and applying quality assessment criteria to included studies, as well as key details of trials included in the MTC, were not adequately described. In addition, some input parameters into the modelling process are incorrect. The ERG was unable to correct all of these mistakes and the impact on the model results is therefore unknown. The National Institute for Health and Clinical Excellence guidance issued as a result of the STA states that DBG is recommended as an option for the primary prevention of VTE events in adults who have undergone elective total hip or knee replacement surgery.

[1]  G. Mowatt,et al.  Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP). , 2011, Health technology assessment.

[2]  J. Caprini,et al.  The Oral Direct Thrombin Inhibitor, Dabigatran Etexilate, is Effective and Safe for Prevention of Major Venous Thromboembolism After Major Orthopedic Surgery , 2008 .

[3]  S. Frostick,et al.  Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial , 2007, Journal of thrombosis and haemostasis : JTH.

[4]  S. Frostick,et al.  Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial , 2007, The Lancet.

[5]  J. Norrie.  Trials of venous thromboembolism prevention , 2007, The Lancet.

[6]  Mark Stevenson,et al.  Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis. , 2006, Health technology assessment.

[7]  O. Linder,et al.  Post‐thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months , 2006, Journal of thrombosis and haemostasis : JTH.

[8]  M Gent,et al.  Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high‐risk abdominal surgery , 2005, The British journal of surgery.

[9]  H. Büller,et al.  A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial , 2005, Journal of thrombosis and haemostasis : JTH.

[10]  A. Lloyd,et al.  Economic evaluation of enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients , 2004, Pharmacy World and Science.

[11]  M. Prins,et al.  The long term clinical course of acute deep vein thrombosis of the arm: prospective cohort study , 2004, BMJ : British Medical Journal.

[12]  E. Minar,et al.  The risk of recurrent venous thromboembolism in men and women. , 2004, The New England journal of medicine.

[13]  R. White,et al.  Low‐Molecular‐Weight Heparins: Are they all the Same? , 2003, British journal of haematology.

[14]  Douglas G Altman,et al.  Interaction revisited: the difference between two estimates , 2003, BMJ : British Medical Journal.

[15]  C. Pashos,et al.  Results of an economic model to assess the cost-effectiveness of enoxaparin, a low-molecular-weight heparin, versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States. , 2002, Clinical therapeutics.

[16]  B. Eriksson,et al.  Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. , 2002, Archives of internal medicine.

[17]  Alain Leizorovicz,et al.  Current Controlled Trials in Cardiovascular Medicine , 2002 .

[18]  B. Eriksson,et al.  Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. , 2001, The New England journal of medicine.

[19]  I Olkin,et al.  Simple Pooling versus Combining in Meta-Analysis , 2001, Evaluation & the health professions.

[20]  L. Lopez.  Low‐Molecular‐Weight Heparins Are Essentially the Same for Treatment and Prevention of Venous Thromboembolism , 2001, Pharmacotherapy.

[21]  L. Melton,et al.  Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based study. , 2001, Journal of vascular surgery.

[22]  M Eccles,et al.  How patients with atrial fibrillation value different health outcomes: a standard gamble study. , 2001, Journal of health services research & policy.

[23]  E. Minar,et al.  Post-thrombotic syndrome after primary event of deep venous thrombosis 10 to 20 years ago. , 2001, Thrombosis research.

[24]  I. Olkin,et al.  Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement , 1999, The Lancet.

[25]  G. Richardson,et al.  Economic evaluation of enoxaparin as postdischarge prophylaxis for deep vein thrombosis (DVT) in elective hip surgery. , 1999, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[26]  Samuel Z Goldhaber,et al.  Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) , 1999, The Lancet.

[27]  R. Kay.  Statistical Principles for Clinical Trials , 1998, The Journal of international medical research.

[28]  George Davey Smith,et al.  Meta-analysis: Principles and procedures , 1997, BMJ.

[29]  H. Wollersheim,et al.  Clinical and haemodynamic sequelae of deep venous thrombosis: retrospective evaluation after 7-13 years. , 1997, Clinical science.

[30]  A. Bollinger,et al.  On the Relationship between Changes in the Deep Veins Evaluated by Duplex Sonography and the Postthrombotic Syndrome 12 Years after Deep Vein Thrombosis , 1997, Thrombosis and Haemostasis.

[31]  C. Samama,et al.  Low molecular weight heparin associated with spinal anaesthesia and gradual compression stockings in total hip replacement surgery. Arar Study Group. , 1997, British journal of anaesthesia.

[32]  D. Bergqvist,et al.  Cost of Long-Term Complications of Deep Venous Thrombosis of the Lower Extremities: An Analysis of a Defined Patient Population in Sweden , 1997, Annals of Internal Medicine.

[33]  F. Piovella,et al.  [Clinical course and incidence of post-thrombophlebitic syndrome after profound asymptomatic deep vein thrombosis. Results of a transverse epidemiologic study]. , 1997, Minerva cardioangiologica.

[34]  A. Connors,et al.  Thirty-day case-fatality rates for pulmonary embolism in the elderly. , 1996, Archives of internal medicine.

[35]  C. Bulstrode,et al.  Thromboprophylaxis and death after total hip replacement. , 1996, The Journal of bone and joint surgery. British volume.

[36]  F. Regan,et al.  Deep venous thrombosis prophylaxis with low molecular weight heparin and elastic compression in patients having total hip replacement. A randomised controlled trial. , 1996, International angiology : a journal of the International Union of Angiology.

[37]  P. Bossuyt,et al.  Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. , 1996, The New England journal of medicine.

[38]  R. Beyth,et al.  Long-term outcomes of deep-vein thrombosis. , 1995, Archives of internal medicine.

[39]  M. Monreal,et al.  Venographic assessment of deep vein thrombosis and risk of developing post‐thrombotic syndrome: a prospective study , 1993, Journal of internal medicine.

[40]  W. Geerts,et al.  Prevention of Deep Vein Thrombosis after Major Knee Surgery - A Randomized, Double-Blind Trial Comparing a Low Molecular Weight Heparin Fragment (Enoxaparin) to Placebo , 1992, Thrombosis and Haemostasis.

[41]  J. Hirsh,et al.  A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. , 1986, The New England journal of medicine.

[42]  D. Lawrence,et al.  Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis. A prospective study. , 1985, American journal of surgery.

[43]  C. Howie,et al.  Assessment of a self-administration protocol for extended subcutaneous thromboprophylaxis in lower limb arthroplasty. , 2006, The Journal of bone and joint surgery. British volume.

[44]  E. Masuda,et al.  Comparing Short-Term Outcomes of Femoral-Popliteal and Iliofemoral Deep Venous Thrombosis: Early Lysis and Development of Reflux , 2005, Annals of vascular surgery.

[45]  C. Pashos,et al.  Economic burden of long-term complications of deep vein thrombosis after total hip replacement surgery in the United States. , 2003, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[46]  Ann Netten,et al.  Unit Costs of Health and Social Care 2002 , 2000 .

[47]  P. Prandoni,et al.  The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. , 1997, Haematologica.

[48]  Leslie Lenert,et al.  Jamia Original Investigations Automated Computer Interviews to Elicit Utilities: Potential Applications in the Treatment of Deep Venous Thrombosis , 2022 .