Finding the Best VTE Prophylaxis Options for Patients Undergoing Total Hip and Knee Replacement

For prophylaxis against venous thromboembolism (VTE) after total hip replacement (THR) or total knee replacement (TKR), guidelines from the American College of Chest Physicians have traditionally recommended fondaparinux or low-molecular-weight heparin (LMWH) over aspirin. With emerging evidence that direct oral anticoagulants (DOACs) are convenient and effective options for these patients, the guidelines expanded the choice to include DOACs and aspirin. However, the lack of comparative-effectiveness research for these options means that there is no clear favorite.

In a literature review published in the Journal of Thrombosis and HaemostasisAlok Kapoor, MD, from the University of Massachusetts Medical School, and co-authors analyzed 12 prophylactic regimens for this patient population, finding that DOACs have a better safety and efficacy profile than higher-potency agents such as fondaparinux, LMWH, and vitamin K antagonists (VKAs). These newer agents also did not significantly increase the risk of hemorrhage.

The researchers conducted a search of OVID Medline, the Cochrane Library, and ClinicalTrials.gov to identify 94 English-language, randomized, controlled trials published between January 1990 and June 2016 that compared the following VTE prophylaxis options in the THR and TKR patient population:

  • fondaparinux
  • direct thrombin inhibitors
  • DOACs (oral direct factor Xa inhibitors and oral direct thrombin inhibitors)
  • LMWH at twice-daily dosing (high LMWH)
  • LMWH at once-daily dosing (enoxaparin 40 mg or dalteparin 5,000 IU/day; low LMWH)
  • VKAs titrated to an international normalized ratio (INR) of 2-3
  • VKAs titrated to an INR of <2
  • unfractionated heparin
  • aspirin
  • dynamic mechanical options (i.e., intermittent pneumatic compression of leg or foot)
  • static mechanical options (i.e., compression stockings)
  • no antithrombic or mechanical compression

Most studies (90%) included older patients with a mean age of >60 years, and more than half of studies (57%) had industry sponsorship.

The two largest studies included low LMWH; because this was the most common comparator in the studies, it served as the reference comparator.

For deep vein thrombosis (DVT), relative to low LMWH, DOACs were the most effective at preventing VTE, resulting in 53 to 139 fewer VTE events per 1,000 patients. Aspirin performed equivalently, relative to low LMWH. The use of VKA titrated to an INR of 2-3, however, was associated with 56 percent more DVT events (48-101 events per 1,000 patients).

“There does not seem to be a compelling reason for professional societies to continue to suggest [aspirin] as a prophylaxis option for the average patient undergoing THR and TKR,” the authors observed. (See TABLE for all outcomes.)

Relative to low LMWH, DOACs demonstrated a trend toward increased hemorrhage, resulting in 0.5 to 6 more events per 1,000 patients, but this association was not statistically significant (p value not provided). VKA titrated to an INR of 2-3 and aspirin performed equivalently, relative to low LMWH.

For symptomatic DVT, relative to low LMWH, DOACs led to four-fold fewer events, translating to 1.5 to 15 fewer events per 1,000 patients.

Fondaparinux, direct thrombin inhibitors, and high LMWH did not have more favorable safety or efficacy profiles, compared with low LMWH.

“All other strategies were inferior to DOACs, except for aspirin,” the authors concluded, which non-significantly reduced the risk of hemorrhage compared with low LMWH (odds ratio = 0.88; 95% CI 0.35-2.22).

The results of this study diverge from the evidence used to guide recommendations set forth by CHEST and the American Academy of Orthopaedic Surgeons, likely because the societies prioritized prevention of symptomatic VTE over prevention of a major hemorrhage that does not result in disruption of care, or used an older definition of hemorrhage, the researchers noted. “Clinicians agreeing with our approach should limit selection of prophylaxis options to those we identified with better profiles,” the authors concluded.

“Small study numbers and low event rates limit the conclusions we can draw about the other options,” the researchers noted. “Low numbers also prohibit our ability to make firm conclusions about the relative effectiveness of prophylaxis options for preventing non-fatal pulmonary embolism.”

The study also is limited by variations in the study designs and the small number of non-industry-sponsored studies, which could have affected the comparison.


Reference

Kapoor A, Ellis A, Shaffer N, et al. Comparative effectiveness of venous thromboembolism prophylaxis options for the patient undergoing total hip and knee replacement: a network meta-analysis. J Thromb Haemost. 2017;15:284-94.

TABLE. Primary and Secondary Outcomes for Prophylaxis Options
Primary Outcomes Secondary Outcomes
Total DVT OR Major Hemorrhage OR Symptomatic DVT OR Non-Fatal PE OR
Fondaparinux

0.50

(95% CI 0.29-0.87)

2.25

(95% CI 1.21-4.47)

3.09

(95% CI 0.94-14.66)

3.44

(95% CI 0.36-54.44)

Oral direct factor Xa inhibitor

0.45

(95% CI 0.35-0.57)

1.21

(95% CI 0.79-1.90)

0.25

(95% CI 0.13-0.47)

0.50

(95% CI 0.16-1.41)

Thrombin inhibitor

0.78

(95% CI 0.58-1.05)

1.45

(95% CI 0.93-2.24)

0.69

(95% CI 0.35-1.36)

0.80

(95% CI 0.26-2.51)

High LMWH

0.73

(95% CI 0.57-0.95)

1.60

(95% CI 1.11-2.38)

0.46

(95% CI 0.23-0.99)

0.44

(95% CI 0.12-1.17)

Low LMWH Reference Reference Reference Reference
VKA (INR 2-3)

1.56

(95% CI 1.14-2.14)

0.93

(95% CI 0.63-1.40)

1.44

(95% CI 0.72-2.86)

1.44

(95% CI 0.29-6.65)

VKA (INR <2)

9.50

(95% CI 2.21-51.59)

2.74

(95% CI 0.06-100.12)

0

(95% CI 0-2.16e+14)

0

(95% CI 0-2.44e+06)

Heparin

1.34

(95% CI 0.94-1.96)

1.89

(95% CI 1.07-3.38)

3.11

(95% CI 0.93-12.29)

4.18

(95% CI 0.97-23.13)

Aspirin

0.80

(95% CI 0.34-1.86)

1.08

(95% CI 0.47-2.42)

2.04

(95% CI 0.56-7.38)

3.97

(95% CI 0.31-68.64)

Dynamic mechanical

1.17

(95% CI 0.76-1.78)

0.15

(95% CI 0.03-0.56)

1.08

(95% CI 0.11-12.11)

0.62

(95% CI 0.04-8.36)

Static mechanical

1.82

(95% CI 0.70-4.70)

0

(95% CI 0-0.24)

Not reported

7.96

(95% CI 0.13-758.37)

Placebo

2.86

(95% CI 2.18-3.76)

1.10

(95% CI 0.54-2.16)

2.64

(95% CI 1.23-5.58)

4.13

(95% CI 1.33-16.40)

DVT = deep vein thrombosis; OR = odds ratio; PE = pulmonary embolism;
LMWH = low-molecular-weight heparin; VKA = vitamin K antagonist;
INR = international normalized ratio

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