Conclusion: Low Molecular Weight Heparin (eg Lovenox) is NOT superior to other anticoagulants currently for preventing blood clots in legs after total hip or knee replacements.

Summary: Enoxaparin does NOT produce an improvement in the prevention of deep-vein thrombosis after total hip or knee replacement surgery as compared with non-LMWH, pharmacologic and nonpharmacologic approaches. Furthermore, enoxaparin has been associated with increased bleeding-related complications in comparison with other antithrombotic approaches. It should be noted that favorable results with enoxaparin were published no later than the earlier part of the previous decade, whereas unfavorable results were published after 2005.

METHOD: A question is asked whether the low molecular weight heparin (LMWH), enoxaparin (eg., Lovenox®) is more effective than other anticoagulant approaches at preventing deep-vein thrombosis (DVT) in patients who undergo total hip or knee arthroplasty. The peer-reviewed literature was searched for English language papers that describe prospectively designed, randomized controlled trials that compare the use of enoxaparin vs. non-LMWH antithrombotic approaches in this patient population. For the purpose of evaluating study outcome (ie. prevention of DVT) neutrality, p ? 0.05 was considered to be statistically insignificant.

LITERATURE SEARCH RESULTS: A total of 10 prospectively designed, randomized controlled trials met the search criteria. Comparators included other anticoagulants such as low-dose aspirin, as well as other pressure-based approaches such as a foot pump or compression.

PREVENTION OF DVT AFTER HIP OR KNEE REPLACEMENT

Over one half of the 10 studies (6 total; Senoran, 2006; Eriksson, 2003; Danish Enoxaparin Study Group, 1991; Warwick, 1998; Avikainen, 1995; Fauno, 1994) showed that enoxaparin was not meaningfully different from comparators in preventing DVT. Positive results were demonstrated with enoxaparin in 2 studies (Colwell, 2003; Fitzgerald, 2001) and negative results in 2 studies (Turpie, 2009; Gelfer, 2006) in comparison with other approaches. Antithrombotic approaches were associated with side effects, and increased bleeding (Fitzgerald, 2001) and soft tissue effects (Warwick, 1998) has been observed with enoxaparin in comparison with those effects with other anticoagulants.

In conclusion, the preponderance of evidence suggests a high level of evidence for a negative predictive value for improved prevention of deep-vein thrombosis with enoxaparin vs. other antithrombotic approaches. Furthermore, enoxaparin has been associated with increased bleeding-related effects in comparison with other agents.

ENOXAPARIN VS. NON-LMWH APPROACHES FOR PREVENTION OF DEEP-VEIN THROMBOSIS AFTER HIP OR KNEE REPLACEMENT:
Studies Favorable: Total 2

Level I: 2 Studies

1. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study.
Colwell, C. W., Jr., S. D. Berkowitz, et al. (2003).
J Thromb Haemost 1(10): 2119-30.
The novel, oral direct thrombin inhibitor ximelagatran failed to demonstrate noninferiority as compared with enoxaparin in terms of venous thromboembolism, resulting in superiority of the enoxaparin regimen. Bleeding rates were similar.

2. Prevention of venous thromboembolic disease following primary total knee arthroplasty. A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin.
Fitzgerald, R. H., Jr., T. E. Spiro, et al. (2001).
J Bone Joint Surg Am 83-A(6): 900-6.
Deep-vein thrombosis occurred more frequently with dose-adjusted warfarin than it did with enoxaparin (45% vs. 25%, p = 0.0001, N = 349). One case of pulmonary embolism occurred in the warfarin group. Hemorrhagic complications were greater in the enoxaparin group, but did not reach statistical significance.

ENOXAPARIN VS. NON-LMWH APPROACHES FOR PREVENTION OF DEEP-VEIN THROMBOSIS AFTER HIP OR KNEE REPLACEMENT
Studies Unfavorable: Total 2

Level I: 2 Studies

1. Deep vein thrombosis prevention in joint arthroplasties: continuous enhanced circulation therapy vs low molecular weight heparin.
Gelfer, Y., H. Tavor, et al. (2006).
J Arthroplasty 21(2): 206-14.
A pneumatic device combined with aspirin was more effective than enoxaparin at preventing deep-vein thrombosis. Safety profiles were similar.

2. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.
Turpie, A. G., M. R. Lassen, et al. (2009).
Lancet 373(9676): 1673-80.
Oral rivaroxaban was shown to be superior to enoxaparin for the prevention of venous thromboembolism. Major bleeding was greater with rivaroxaban but did not reach statistical significance.

ENOXAPARIN VS. NON-LMWH APPROACHES FOR PREVENTION OF DEEP-VEIN THROMBOSIS AFTER HIP OR KNEE REPLACEMENT
Studies Neutral: Total 13

Level I: 6 Studies

1. Low molecular weight heparin (enoxaparin) compared with unfractionated heparin in prophylaxis of deep venous thrombosis and pulmonary embolism in patients undergoing hip replacement.
Avikainen, V., H. von Bonsdorff, et al. (1995).
Ann Chir Gynaecol 84(1): 85-90.
There were more cases of deep-vein thrombosis with unfractionated heparin than with enoxaparin, but statistical significance was not reached (“P > 0.05”). The cut-off for statistical significance (P = 0.05) was of the weakest level of evidence.

2. Low-molecular-weight heparin (enoxaparin) vs dextran 70. The prevention of postoperative deep vein thrombosis after total hip replacement. The Danish Enoxaparin Study Group.
DESG (1991).
Arch Intern Med 151(8): 1621-4.
Study is small (N = 70). Although enoxaparin was associated with fewer cases of deep vein thrombosis than was dextran 70, pulmonary embolism and bleeding rates were similar. None of the patients died in the hospital. One patient in the enoxaparin group died 15 days after surgery.

3. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement.
Eriksson, B. I., G. Agnelli, et al. (2003).
Thromb Haemost 89(2): 288-96.
This study uses a substandard cutoff for statistical significance, ie. p = 0.53 was considered sufficient evidence to support favorable results with enoxaparin vs. melagatran followed by oral ximelagatran. Additionally, bleeding rates were comparable.

4. Prophylaxis for the prevention of venous thromboembolism after total knee arthroplasty. A comparison between unfractionated and low-molecular-weight heparin.
Fauno, P., O. Suomalainen, et al. (1994).
J Bone Joint Surg Am 76(12): 1814-8.
Results with enoxaparin and unfractionated heparin were comprehensively similar.

5. Enoxaparin and heparin comparison of deep vein thrombosis prophylaxis in total hip replacement patients.
Senaran, H., E. Acaroglu, et al. (2006).
Arch Orthop Trauma Surg 126(1): 1-5.
Rates of deep-vein thrombosis were the same in the enoxaparin and unfractionated heparin groups. Discontinuations in unfractionated heparin were reported.

6. Comparison of the use of a foot pump with the use of low-molecular-weight heparin for the prevention of deep-vein thrombosis after total hip replacement. A prospective, randomized trial.
Warwick, D., J. Harrison, et al. (1998).
J Bone Joint Surg Am 80(8): 1158-66.
The foot pump was concluded to be a suitable alternative to low-molecular-weight heparin for prophylaxis against thromboembolism, as the rates of deep-vein thrombosis were similar between groups. The foot pump produced fewer soft-tissue side effects.

LEVEL I

Randomized, controlled clinical trials. Researchers would use a computer program to randomly assign patients with back pain into two groups of 20. The first group (placebo group known as the control) would drink water (that only tasted like pomegranate juice but was not) for 10 days. The second group would drink real pomegranate juice for 10 days. None of the patients would know if they were drinking the real pomegranate juice or not. (This is called a blinded study). Then a researcher who does not know which person drank what (which now makes this a what’s called a “double blinded” study) would interview the patients to determine if their back pain was reduced, worsened or stayed the same. After this was all done, the information about which patients drank what would then be revealed. One could then see if those who drank the real pomegranate juice were better or not than the water drinking group.

LEVEL II

Non-randomized, prospective comparative study. A researcher looks at 40 patients medical records to select 20 patients for the pomegranate drinking group and 20 patients for the control group who will drink water. This is called a “cohort,” namely a control and experimental patient make a cohort. Here the researcher may introduce his own bias whether he intends to or not. If he believes pomegranate is a safe, effective treatment for back pain then whether he means to or not he may put the healthier patients with less back pain in the pomegranate group and patients complaining of more back pain in the water-drinking group. (This particular bias is called “selection bias.” See section on types of research bias.)

LEVEL III

Retrospective (already occurred) comparative study or case controlled study (each “experimental“ patient is matched to a patient that never had the experimental). This is not a reliable standard for determining one treatment over another, though it can be helpful to, say, see how many complications a certain treatment has. Researchers do a retrospective study for example reviewing 20 patient records of patients who reported they have been drinking pomegranate juice in the past and then 20 patients who have not reported drinking pomegranate juice. Then the researchers review the patients’ medical records determine if the back pain was reported better, worse or stayed the same. Here again, the selection process may introduce bias intentionally or not. In this case it may not only be selection bias, but could involve “recall” bias, or “expectation bias” or “attention bias.” (See Bias in Research section).

LEVEL IV

Case series do not determine success or failure of a treatment compared to other treatments or no treatment at all. Researchers or a physician does a case study on 20 patients who drink pomegranate juice for 10 days and then report the results. In this case there is no control group or comparison to patients who are not drinking pomegranate juice. It does not take into consideration that back pain could get better in 10 days if the patient takes nothing at all for the pain. These studies are easier and cheaper. They can be of value to determine better methods of doing a particular treatment, or what the complications of a certain treatment are, but NOT for determining if one treatment is better than another.

LEVEL V

Expert opinion. One physician expert’s opinion on if pomegranate juice helps reduce back pain. No original research is conducted. Instead, just a written opinion or editorial that may talk about other research and give opinions, but no clinical study is conducted. AME considers this to be one step above hearsay for determining one treatment over another, though it may be valuable for stimulating discussion and ideas on a particular topic.

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