Postorthopedic Anticoagulation a Double-Edged Sword

Troy Brown

May 14, 2012

May 14, 2012 — A systematic review suggests that a prolonged course of anticoagulation after major orthopedic surgery decreases the risk for venous thromboembolism (VTE) but increases the risk for minor bleeding.

Diana M. Sobieraj, PharmD, from the University of Connecticut/Hartford Hospital Evidence-Based Practice Center, and colleagues conducted a systematic review to determine the optimal duration of thromboprophylaxis for patients undergoing major orthopedic surgery: total hip replacement (THR), total knee replacement (TKR), or hip fracture surgery (HFS). Their results are published in the May 15 issue of the Annals of Internal Medicine.

Given the risk for developing VTE following major orthopedic surgery, patients are usually treated with a short course of anticoagulation, and are believed to no longer need it once they become ambulatory or are discharged from the hospital. Some trials, however, suggest that a longer course of thromboprophylaxis is more effective at preventing pulmonary embolism (PE), mortality, and postthrombotic syndrome.

Most clinical trials have been underpowered to conclusively assess the potential benefits and harms associated with prolonged thromboprophylaxis. Systematic reviews that have assessed prolonged thromboprophylaxis for patients having major orthopedic surgery in the past have either had conflicting results or failed to pool data on potential harms.

The authors searched the Cochrane Central Register of Controlled Trials and Scopus from 1980 to July 2011 and MEDLINE from 1980 through November 2011.

Studies were included if they were randomized controlled trials of patients undergoing THR, TKR, or HFS and if they reported data for any benefit or harm. Studies needed to compare the same pharmacologic agent and dose given either for a prolonged period of 21 days or the standard duration of 7 to 10 days. The agents evaluated needed to have a current US Food and Drug Administration indication.

Eight randomized trials with a total of 2917 participants met inclusion criteria comparing thromboprophylaxis of standard (7 - 10 days) or prolonged (21 days) duration after major orthopedic surgery in adults.

Studies included in the review had objectively confirmed VTE by "Doppler ultrasonography or venography for DVT and spiral computed tomography, angiography, or ventilation–perfusion scanning with either Prospective Investigation of Pulmonary Embolism Diagnosis criteria or high clinical suspicion based on symptoms for PE," write the authors. "Trials that did not meet diagnostic imaging criteria for DVT- or PE-related outcomes but reported on harms were included for harms outcomes only."

Quality of Trials

Three of the trials were classified as good quality, with adequate randomization and concealed allocation procedures; blinded patients, providers, and event adjudicators; groups that had similar baseline characteristics; reporting of complete follow-up and use of intention-to-treat analyses; and reporting of conflicts of interest.

The other 5 trials were classified as "fair." In 1 trial classified as fair quality, patients and providers were not clearly blinded. In the other 4 "fair" trials, randomization and allocation concealment techniques were not reported.

High strength of evidence showed that patients who underwent prolonged prophylaxis experienced fewer PEs (odds ratio [OR], 0.14; 95% confidence interval [CI], 0.04 - 0.47; absolute risk reduction [ARR], 0.8%) and asymptomatic DVTs (relative risk [RR], 0.48; 95% CI, 0.31 - 0.75; ARR, 5.8%), symptomatic DVTs (OR, 0.36; 95% CI, 0.16 - 0.81; ARR, 1.5%), and proximal DVTs (RR, 0.29; 95% CI, 0.16 - 0.52; ARR 7.1%) than patients treated for the standard duration. High strength of evidence also showed, however, that prolonged anticoagulation increased the odds of minor bleeding (OR, 2.44; 95% CI, 1.41 - 4.20).

Moderate strength of evidence indicated fewer symptomatic, objectively confirmed VTEs (RR, 0.38; 95% CI, 0.19 - 0.77; ARR, 5.7%), nonfatal PEs (OR, 0.13; 95% CI, 0.03 - 0.54; ARR, 0.7%), and DVTs (RR, 0.37; 95% CI, 0.21 - 0.64; ARR, 12.1%) with prolonged anticoagulation.

Data on nonfatal PE reductions with prolonged anticoagulation were rated as moderate strength because most of the relevant pooled trials were of fair quality as a result of inadequate randomization and allocation concealment.

The strength of evidence for symptomatic objectively confirmed VTE and DVT was rated as moderate because of inconsistency (the I 2 values were high, at 69% and 78%, respectively).

The direction of effect was consistent across trials for both outcomes, but the magnitude of benefit differed, possibly because of differences in the length of prolonged prophylaxis, the different drugs evaluated, the surgical subpopulation assessed, or variability during surveillance screening.

Balance of Benefits vs Harms Favorable

"Our findings suggest that the balance of benefits and harms is favorable for prolonged versus standard-duration prophylaxis in patients undergoing major orthopedic surgery. Prolonged prophylaxis reduced the occurrence of symptomatic VTE, PE, and DVT while increasing the risk for minor bleeding. This evidence is derived primarily from trials of patients undergoing THR surgery," the authors write.

Study limitations include "scant and insufficient" data relevant to knee replacement or hip fracture surgery. In addition, most trials included few events; therefore, the strength of evidence ratings used may not "adequately capture uncertainty in such situations," the researchers note.

In a related editorial, Marc Carrier, MD, an associate professor in the Department of Medicine, Faculty of Medicine, and a research chair in Venous Thromboembolism and Cancer (Tier 2) at the University of Ottawa in Ontario, Canada, and Mary Cushman, MD, a professor at the University of Vermont College of Medicine, in Burlington, write, "These findings confirm the [American College of Chest Physicians] guideline recommendation that suggested extending thromboprophylaxis for up to 35 days after major orthopedic surgery and add a considerable contribution by specifically reporting the evidence according to the type of major orthopedic surgery."

They continue, "Detection of DVT on screening probably reduces subsequent detection of some symptomatic VTE, leading to underestimation of efficacy on patient-important outcomes. The risk for VTE associated with surgery extends for months afterward, so onset of VTE beyond discontinuation of thromboprophylaxis in trials that do not use screening imaging for DVT should be studied."

"We hope that future clinical trials will address the full range of outcomes of thromboprophylaxis in orthopedic surgery patients, including death, symptomatic VTE in the months after surgery among patients who were not screened for asymptomatic DVT, clinically important bleeding, the postthrombotic syndrome, and quality of life," the editorialists conclude.

The University of Connecticut/Hartford Hospital Evidence-based Practice Center supported the study with funding from the Agency for Healthcare Research and Quality. One study author reports receiving grants or grants pending from Janssen Pharmaceuticals, a consulting fee or honorarium from Janssen Pharmaceuticals, and a consultancy with Acorda Therapeutics. Another reports payment for lectures including service on speakers bureaus from Janssen Pharmaceuticals. Dr. Carrier and Dr. Cushman have disclosed no relevant financial relationships.

Ann Intern Med. 2012;156:720-727.

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