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Oral Direct Factor Xa Inhibitors Versus Low-Molecular-Weight Heparin to Prevent Venous Thromboembolism in Patients Undergoing Total Hip or Knee Replacement: A Systematic Review and Meta-analysis

Ignacio Neumann, MD; Gabriel Rada, MD; Juan Carlos Claro, MD; Alonso Carrasco-Labra, DDS; Kristian Thorlund, PhD; Elie A. Akl, MD, MPH, PhD; Shannon M. Bates, MD, MSc; and Gordon H. Guyatt, MD, MSc
[+] Article and Author Information

From McMaster University Health Sciences Centre, Hamilton, Ontario, Canada, State University of New York at Buffalo, Buffalo, New York, and Evidence Based Health Care Program, Pontificia Universidad Católica de Chile, Santiago, Chile.

Acknowledgment: The authors thank Jo-Anne Petropoulos for her help in developing the search strategy and the authors of the trials who kindly provided additional data.

Potential Conflicts of Interest: Dr. Guyatt: Consultancy (money to institution): Bristol-Myers Squibb; Grants/grants pending (money to institution): Canadian Institutes of Health Research. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2601.

Requests for Single Reprints: Ignacio Neumann, MD, McMaster University Health Sciences Centre, Clinical Epidemiology & Biostatistics, Room 2C12, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada; e-mail, mailto:ignacio.neumann@gmail.com.

Current Author Addresses: Drs. Neumann, Carrasco-Labra, Thorlund, and Guyatt: McMaster University Health Sciences Centre, Clinical Epidemiology & Biostatistics, Room 2C12, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

Drs. Rada and Claro: Evidence Based Health Care Program, Pontificia Universidad Católica de Chile, Lira 63, Santiago, Chile.

Dr. Akl: Department of Medicine, State University of New York at Buffalo, 462 Grider Street, ECMC-CC 142, Buffalo, NY 14215.

Dr. Bates: Department of Medicine, McMaster University Health Sciences Centre, Room 3W11, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

Author Contributions: Conception and design: I. Neumann, J.C. Claro, G.H. Guyatt.

Analysis and interpretation of the data: I. Neumann, K. Thorlund, E.A. Akl, G.H. Guyatt.

Drafting of the article: I. Neumann, G.H. Guyatt.

Critical revision of the article for important intellectual content: I. Neumann, G. Rada, J.C. Claro, K. Thorlund, E.A. Akl, S.M. Bates, G.H. Guyatt.

Final approval of the article: I. Neumann, G. Rada, J.C. Claro, A. Carrasco-Labra, E.A. Akl, S.M. Bates, G.H. Guyatt.

Statistical expertise: K. Thorlund.

Administrative, technical, or logistic support: I. Neumann.

Collection and assembly of data: I. Neumann, G. Rada, J.C. Claro, A. Carrasco-Labra.


Ann Intern Med. 2012;156(10):710-719. doi:10.7326/0003-4819-156-10-201205150-00421
Text Size: A A A

Background: Thromboembolic disease is the most frequent medical complication of arthroplasty.

Purpose: To evaluate the benefits and harms of oral direct factor Xa inhibitors versus low-molecular-weight heparin (LMWH) in patients undergoing total hip or knee replacement.

Data Sources: MEDLINE (1966 to December 2011), EMBASE (1980 to December 2011), and the Cochrane Central Register of Controlled Trials (up to December 2011), without language restrictions. References of reviews and abstracts of conferences were hand-searched.

Study Selection: Randomized trials in patients undergoing hip or knee replacement that evaluated factor Xa inhibitors versus LMWH.

Data Extraction: Two reviewers independently evaluated eligibility, abstracted the data, and assessed risk for bias.

Data Synthesis: In 22 trials, high-quality evidence indicated that the absolute effect of factor Xa inhibitors and LMWH does not differ in terms of all-cause mortality (risk difference, 0 fewer deaths per 1000 patients [95% CI, 2 fewer to 1 more death]) or nonfatal pulmonary embolism (risk difference, 0 fewer events per 1000 patients [CI, 1 fewer to 2 more events]). Factor Xa inhibitors can prevent 4 instances of symptomatic deep venous thrombosis per 1000 treated patients (CI, 3 to 6 fewer events; high-quality evidence) but may increase major bleeding by 2 more events per 1000 patients (CI, 0 to 4 more events; moderate-quality evidence). High, but not lower, doses of oral factor Xa inhibitors increased bleeding compared with LMWH.

Limitations: Most trials did not report outcome data for a substantial proportion of the patients. In 9 trials, the follow-up period was 14 days or less.

Conclusion: Compared with LMWH, lower doses of oral factor Xa inhibitors can achieve a small absolute risk reduction in symptomatic deep venous thrombosis without increasing bleeding.

Primary Funding Source: None.

Figures

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Figure 1.

Summary of evidence search and selection.

RCT = randomized, controlled trial.

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Figure 2.

Mortality up to 10 weeks with oral direct factor Xa inhibitors versus LMWH.

ADVANCE = Apixaban Dose Orally vs. Anticoagulant with Enoxaparin; LMWH = low-molecular-weight heparin; ODIXa = Oral DIrect factor Xa inhibitor; RECORD = Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism.

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Figure 3.

Symptomatic deep venous thrombosis up to 5 weeks with oral direct factor Xa inhibitors versus LMWH.

ADVANCE = Apixaban Dose Orally vs. Anticoagulant with Enoxaparin; APROPOS = Apixaban Prophylaxis in Patients undergoing total knee replacement Surgery; EXPERT = A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement; LMWH = low-molecular-weight heparin; ODIXa = Oral DIrect factor Xa inhibitor; ONYX = Oral direct iNhibition by YM150 of factor Xa; RECORD = Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism.

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Comments

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Oral direct factor Xa inhibitor vs low molecular weight heparin (LMWH) to prevent venous thrombolism in patients undergoing total hip or knee replacement
Posted on May 22, 2012
Krishna, Ghimire, Academic Hospitalist
Mercy Medical Center- North Iowa
Conflict of Interest: None Declared

Dear Editor,

I read an interesting article " Oral direct factor Xa inhibitor vs low molecular weight heparin (LMWH) to prevent venous thrombolism in patients undergoing total hip or knee replacement." By Ignacio Neumann and colleagues published in Annals on May 12, 2012. Deep venous thrombosis (DVT) after total knee replacement (TKR) and total hip replacement (THR) range form 41 % to 85% and 42% to 57% respectively without anticoagulation, which leads to increase in length of hospital stay and substantial increase in health care cost. Most of orthopedicians are still very reluctant to use pharmacological agents for DVT prophylaxis because of risk of bleeding, hematoma formation and delayed wound healing. Aspirin and SCD boots are more commonly used by orthopedicians for DVT prophylaxis. Oral factor Xa antagonist are promising agents to prevent DVT after TKR and THR. But I want to caution about the conclusion made in this article that direct factor Xa inhibitor as compared to LMWH decrease DVT events by 3/1000. It may be premature to come to conclusion without knowing the limitation of studies which were included in meta-analysis. Mean body mass index (BMI) reported in those study included in meta analysis is around 26-32 kg/m2, hence these results cannot be extrapolated to severely obese patients. LMWH dose was not appropriately adjusted for obese patients included in study. The risk of venous thromboembolism after TKR is around 2 weeks and after THR is around 4-6 weeks but DVT prophylaxis was given only for 7-10 days in some of the studies included in meta analysis. If Renal failure and liver failure patients were included in study it may have skewed the outcome as well. Absolute reduction of DVT is also a very small number.

Conflict of Interest:

None declared

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