DATE: 06 May 2013 CONTEXT AND POLICY ISSUES

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1 TITLE: Low Molecular Weight Heparins versus New Oral Anticoagulants for Long-Term Thrombosis Prophylaxis and Long-Term Treatment of DVT and PE: A Review of the Clinical and Cost-Effectiveness DATE: 06 May 2013 CONTEXT AND POLICY ISSUES Venous thromboembolism (VTE), the formation of a blood clot in one of the veins of the body, is a common complication in patients undergoing surgical procedures. 1 VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), can be life-threatening and result in longterm morbidity, highlighting the importance of thrombosis prophylaxis. 2 In the absence of prophylaxis, the overall risk of DVT is estimated to be 10-40% in general surgery patients and 40-60% in major orthopedic surgery patients. 1 Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are two of the most commonly performed operations in orthopedic surgery. 3 In addition to surgical procedures, there are other risk factors for developing VTE including malignancies, limited mobility, obesity, pregnancy, myocardial infarction, ischemic stroke, varicose veins, and chronic kidney disease. 4 Low molecular weight heparins (LMWHs) are routinely used as an anticoagulant for thrombosis prophylaxis in both medical and surgical patients. 1,4 LMWHs are administered subcutaneously and four of these drugs have been approved in Canada: enoxaparin, dalteparin, nadroparin, and tinzaparin. In the last decade, several new oral anticoagulants (NOACs) have been developed for thrombosis prophylaxis, offering a more targeted mechanism of anticoagulation. NOACs include the direct thrombin inhibitor dabigatran, and the direct factor Xa inhibitors rivaroxaban and apixaban. 1 The minimum recommended duration for anticoagulation is 10 to 14 days, but extended prophylaxis up to 35 days in the outpatient period after major orthopedic surgery is suggested. 1 Several phase III randomized controlled trials (RCTs) have compared the efficacy and safety of NOACs to LMWHs for thrombosis prophylaxis in patients that have undergone THA and TKA, using a treatment period up to 35 days. 5-8 Studies examining the effect of LMWHs and NOACs for thrombosis prophylaxis in acutely ill medical patients generally have treatment periods between 6 to 14 days, and up to 30 days. 4 Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 The purpose of this review is to examine the comparative clinical and cost-effectiveness of LMWHs used as a single agent versus NOACs for long-term thrombosis prophylaxis and for long-term treatment of DVT and PE. RESEARCH QUESTIONS 1. What is the comparative clinical effectiveness of low molecular weight heparins (LMWHs) used as a single agent versus new oral anticoagulants (NOACs) for long-term thrombosis prophylaxis? 2. What is the cost-effectiveness of LMWHs used as a single agent compared with NOACs for long-term thrombosis prophylaxis? 3. What is the comparative clinical effectiveness of LMWHs use as a single agent versus NOACs for long-term treatment of deep vein thrombosis and/or pulmonary embolism? 4. What is the cost-effectiveness of LMWHs use as a single agent versus NOACs for longterm treatment of deep vein thrombosis and/or pulmonary embolism? KEY FINDINGS No relevant literature was identified regarding the comparative clinical and cost-effectiveness of LMWHs used as a single agent versus NOACs for long-term thrombosis prophylaxis and for long-term treatment of DVT and PE. METHODS A limited literature search was conducted of key resources including Pubmed, The Cochrane Library (2013, Issue 3), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No methodological filters were applied. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2003 and April 8, Literature Search Strategy One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for the final article selection, according to selection criteria presented in Table 1. Selection Criteria and Methods Table 1: Selection Criteria Population Patients on long-term (>38 days) prophylaxis for thrombosis associated with cancer, atrial fibrillation, post-operatively, or other medical conditions. Patients on long-term (>38 days) treatment for DVT and/or PE Intervention Low molecular weight heparins (dalterparin, enoxaparin, nadroparin, tinzaparin) as a single agent LMWHs for Thrombosis Prophylaxis and DVT Treatment 2

3 Comparator Outcomes Study Designs New oral anticoagulants (dabigatran, rivaroxaban, apixaban) Clinical effectiveness, adverse events, cost effectiveness Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), non-randomized studies, and economic evaluations Exclusion Criteria Studies were excluded if they did not meet the selection criteria, were duplicate publications or included in a selected systematic review, or were published prior to SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 271 citations. Upon screening titles and abstracts, 229 citations were excluded and 42 potentially relevant articles were retrieved for full-text review. No additional potentially relevant reports were identified through grey literature searching. Of the 42 potentially relevant reports, none met inclusion criteria. The study selection process is outlined in a PRISMA flowchart (Appendix 1). The majority of studies were excluded because the treatment period did not exceed 38 days. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING No relevant literature was identified; therefore, no conclusions can be presented regarding the comparative clinical and cost-effectiveness of LMWHs used as a single agent versus NOACs for long-term thrombosis prophylaxis and for long-term treatment of DVT and PE. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: LMWHs for Thrombosis Prophylaxis and DVT Treatment 3

4 REFERENCES 1. Riva N, Donadini MP, Bozzato S, Ageno W. Novel oral anticoagulants for the prevention of venous thromboembolism in surgical patients. Thromb Res Jan;131 Suppl 1:S67- S Turun S, Banghua L, Yuan Y, Zhenhui L, Ying N, Jin C. A systematic review of rivaroxaban versus enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thromb Res Jun;127(6): Russell RD, Huo MH. Apixaban and Rivaroxaban decrease deep venous thrombosis but not other complications after total hip and total knee arthroplasty. J Arthroplasty Mar Dobromirski M, Cohen AT. How I manage venous thromboembolism risk in hospitalized medical patients. Blood Aug 23;120(8): Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE- NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost Apr;105(4): Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med [Internet] Jun 26 [cited 2013 Apr 15];358(26): Available from: 7. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet Sep 15;370(9591): Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med Dec 23 ;363(26): LMWHs for Thrombosis Prophylaxis and DVT Treatment 4

5 APPENDIX 1: Selection of Included Studies 271 citations identified from electronic literature search and screened 229 citations excluded 42 potentially relevant articles retrieved for scrutiny (full text, if available) 0 potentially relevant reports retrieved from other sources (grey literature, hand search) 42 potentially relevant reports 42 reports excluded: -irrelevant population (2) -irrelevant intervention and comparator - not long-term treatment (36) -other (review articles, editorials) (4) 0 reports included in review LMWHs for Thrombosis Prophylaxis and DVT Treatment 5