Diana M. Sobieraj, PharmD; Soyon Lee, PharmD; Craig I. Coleman, PharmD; Vanita Tongbram, MBBS, MPH; Wendy Chen, PharmD; Jennifer Colby, PharmD; Jeffrey Kluger, MD; Sagar Makanji, PharmD; Ajibade O. Ashaye, MD, MPH; C. Michael White, PharmD
Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank the members of the key informant and technical expert panel for their contribution and expertise in the development of the key questions and protocol for this review: Yngve Falck-Ytter, MD, Case Western Reserve University School of Medicine, Cleveland, Ohio; Charles W. Francis, MD, University of Rochester School of Medicine, Rochester, New York; Joshua J. Jacobs, MD, Rush Medical College, Chicago, Illinois; J. Samuel Pope, MD, Hartford Hospital, Hartford, Connecticut; and Sandra Zelman Lewis, PhD, American College of Chest Physicians, Northbrook, Illinois. These individuals are not directly responsible for the final content, interpretation, or conclusions of this article.
Grant Support: By the University of Connecticut/Hartford Hospital Evidence-based Practice Center (contract 290-2007-10067-I with the Agency for Healthcare Research and Quality).
Potential Conflicts of Interest: Dr. Coleman: Grants/grants pending (money to institution): Janssen Pharmaceuticals; Consulting fee or honorarium: Janssen Pharmaceuticals; Consultancy: Acorda Therapeutics. Dr. Kluger: Payment for lectures including service on speakers bureaus: Janssen Pharmaceuticals. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2593.
Requests for Single Reprints: C. Michael White, PharmD, Department of Pharmacy, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102; e-mail, mailto:firstname.lastname@example.org.
Current Author Addresses: Drs. Sobieraj, Lee, Coleman, Chen, Makanji, and White: Department of Pharmacy, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102.
Dr. Tongbram: Oxford Outcomes/ICON Plc, 161 Madison Avenue, Suite 205, Morristown, NJ, 07960.
Dr. Colby: Institute for Clinical and Economic Review, 101 Merrimac Street, 3rd Floor, Boston, MA 02114.
Dr. Kluger: Department of Cardiology, Hartford Hospital, 80 Seymour Street, Hartford CT 06102.
Dr. Ashaye: Evidence Review & Synthesis, United BioSource Corporation, 430 Bedford Street, Lexington, MA 02420.
Author Contributions: Conception and design: D.M. Sobieraj, C.I. Coleman, V. Tongbram, C.M. White.
Analysis and interpretation of the data: D.M. Sobieraj, S. Lee, C.I. Coleman, V. Tongbram, J. Kluger, A.O. Ashaye, C.M. White.
Drafting of the article: D.M. Sobieraj, S. Lee, C.I. Coleman, V. Tongbram, C.M. White.
Critical revision of the article for important intellectual content: D.M. Sobieraj, S. Lee, C.I. Coleman, V. Tongbram, J. Kluger, C.M. White.
Final approval of the article: D.M. Sobieraj, S. Lee, C.I. Coleman, V. Tongbram, J. Colby, J. Kluger, A.O. Ashaye, C.M. White.
Provision of study materials or patients: D.M. Sobieraj, S. Lee.
Statistical expertise: D.M. Sobieraj, S. Lee, C.I. Coleman, V. Tongbram.
Obtaining of funding: D.M. Sobieraj, C.I. Coleman, J. Kluger, C.M. White.
Administrative, technical, or logistic support: D.M. Sobieraj, S. Lee, C.I. Coleman, V. Tongbram, J. Colby, S. Makanji, C.M. White.
Collection and assembly of data: D.M. Sobieraj, S. Lee, V. Tongbram, W. Chen, J. Colby, S. Makanji, A.O. Ashaye, C.M. White.
Sobieraj D., Lee S., Coleman C., Tongbram V., Chen W., Colby J., Kluger J., Makanji S., Ashaye A., White C.; Prolonged Versus Standard-Duration Venous Thromboprophylaxis in Major Orthopedic Surgery: A Systematic Review. Ann Intern Med. 2012;156:720-727. doi: 10.7326/0003-4819-156-10-201205150-00423
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Published: Ann Intern Med. 2012;156(10):720-727.
The optimal duration of thromboprophylaxis after major orthopedic surgery is unclear.
To compare the benefits and harms of prolonged versus standard-duration thromboprophylaxis after major orthopedic surgery in adults.
Cochrane Central Register of Controlled Trials and Scopus from 1980 to July 2011 and MEDLINE from 1980 through November 2011, without language restrictions.
Randomized trials reporting thromboembolic or bleeding outcomes that compared prolonged (≥21 days) with standard-duration (7 to 10 days) thromboprophylaxis.
Two independent reviewers abstracted data and rated study quality and strength of evidence.
Eight randomized, controlled trials (3 good-quality and 5 fair-quality) met the inclusion criteria. High-strength evidence showed that compared with standard-duration therapy, prolonged prophylaxis resulted in fewer cases of pulmonary embolism (PE) (5 trials; odds ratio [OR], 0.14 [95% CI, 0.04 to 0.47]; absolute risk reduction [ARR], 0.8%), asymptomatic deep venous thrombosis (DVT) (4 trials; relative risk [RR], 0.48 [CI, 0.31 to 0.75]; ARR, 5.8%), symptomatic DVT (4 trials; OR, 0.36 [CI, 0.16 to 0.81]; ARR, 1.5%), and proximal DVT (6 trials; RR, 0.29 [CI, 0.16 to 0.52]; ARR, 7.1%). Moderate-strength evidence showed fewer symptomatic objectively confirmed episodes of venous thromboembolism (4 trials; RR, 0.38 [CI, 0.19 to 0.77]; ARR, 5.7%), nonfatal PE (4 trials; OR, 0.13 [CI, 0.03 to 0.54]; ARR, 0.7%), and DVT (7 trials; RR, 0.37 [CI, 0.21 to 0.64]; ARR, 12.1%) with prolonged prophylaxis. High-strength evidence showed more minor bleeding events with prolonged prophylaxis (OR, 2.44 [CI, 1.41 to 4.20]; absolute risk increase, 6.3%), and insufficient evidence from 1 trial on hip fracture surgery suggested more surgical-site bleeding events (OR, 7.55 [CI, 1.51 to 37.64]) with prolonged prophylaxis.
Data relevant to knee replacement or hip fracture surgery were scant and insufficient. Most trials had few events; the strength of evidence ratings that were used may not adequately capture uncertainty in such situations.
Prolonged prophylaxis decreases the risk for venous thromboembolism, PE, and DVT while increasing the risk for minor bleeding in patients undergoing total hip replacement.
Agency for Healthcare Research and Quality.
RaghavendraAllareddy, MBBS, MD, MRCP
Center for Rehabilitation and Post Acute Care, Neurological Institute
March 20, 2012
Venous Thromboembolism-Where did the numbers go wrong?
I read the articles by Sobieraj et al (1) and accompanying editorial with great interest and also tumbled across final report of Venous Thromboembolism (VTE) Prophylaxis in Orthopedic Surgery from the Agency for Healthcare Research and Quality (AHRQ), published on March 13th (2). General theme of both articles (1,2) was to recommend VTE prophylaxis for these surgical patients. Interestingly, neither the article (1) nor the final report (2) mentioned any significant mortality benefit with VTE prophylaxis. Even a recent systematic review (3) for American College of Physicians (ACP) evidence- based clinical practice guidelines about VTE prophylaxis in medical and stroke patients, suggested that heparin prophylaxis didn't provide any benefit in total mortality.
How to explain this paradox of significant mortality due to VTE from previous autopsy studies and papers suggesting benefit (4, 5) and lack of mortality benefit in the recent meta-analysis /systematic reviews in both medical and orthopedic surgical patients (1,2,3). Where did the numbers go wrong? Is it due to changes in patient characteristics from randomized trials to real life situation? Are we missing any other major "elephant in the room" like early ambulation [since implementation of diagnosis related -groups (DRG) since1982] or the underestimation of the use and effectiveness of mechanical prophylaxis? If mortality benefits are ignored, the next concern is about the morbidity --symptomatic deep venous thrombosis (DVT) / pulmonary embolism (PE) and the post thrombotic syndrome. Is it worthwhile-both by way of logistics and costs--risking the large number of patients for the concern of morbidity alone? Should we confine ourselves to VTE prophylaxis to only very high risk patients and treat only the symptomatic DVTs and symptomatic PEs, even though we know that both asymptomatic and symptomatic DVTs alike could be causing the post thrombotic syndrome? Do we need to adopt any other newer ways to prevent VTEs and complications like 'more effective' mechanical prophylaxis? Can we avoid the VTE prophylaxis by adopting new ideas-such as using rise in leucocyte counts to initiate evaluation or routine periodic screening by Venous dopplers / venography. Just when we were thinking that a solution to the problem of VTE is 'around the corner' (with advent of new and more powerful drugs), we are have entered an era of New Uncertainties as to what to do! Is there some hope with several newer drugs in pipeline? These are real difficult questions and very few definitive answers! Raghavendra Allareddy, MBBS, MD Cleveland Clinic, Cleveland, OH
1. Sobieraj D, Lee S, Coleman CI, Tongbram V, Chen W, Colby J, et al.. Prolonged versus standard duration venous thromboprophylaxis in major orthopedic surgery. A systematic review. Ann Intern Med. 2012;154.
2. http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for- guides-reviews-and- reports/?pageaction=displayproduct&productid=992&ECem=120313.
3. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Ann Intern Med. 2011 Nov 1;155(9):602-15.
4. Autopsy-verified pulmonary embolism in a surgical department: analysis of the period from 1951 to 1988. Lindblad B, Eriksson A, Bergqvist D Br J Surg. 1991;78(7):849.
5. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. Chest. 2009 Feb;135 (2):513-20. Review.
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