LOW MOLECULAR WEIGHT HEPARIN (LMWH) vs. Either Aspirin or Warfarin For Non-orthopedic Applications
Conclusion: Low molecular weight heparin (eg Lovenox) is NOT better than aspirin or warfarin (Coumadin) as preventing blood clots in legs in general medical conditions.
Summary: Relative to either aspirin or warfarin, low molecular weight heparins (LMWHs) do not produce a meaningful improvement in the prevention of thrombotic complications such as deep-vein thrombosis (DVT) or recurrent miscarriages in settings outside of orthopedics. Medical settings included oncology, pediatrics, and obstetrics; and other relevant studies concerned ischemic and other cardiovascular events, and thrombotic prophylaxis before air travel. While increased bleeding with warfarin may occur relative to LMWH this observation has not been demonstrated conclusively, and these observations did not hold true for the comparisons of aspirin and LMWH.
METHOD: A question is asked whether low molecular weight heparin (LMWH) is more effective than either aspirin or warfarin at preventing thrombotic complications such as deep-vein thrombosis (DVT) or pulmonary embolism (PE) in patient settings outside of the orthopedic arena. The peer-reviewed literature was searched for English language papers that describe prospectively designed, randomized controlled trials that compare the use of any LMWH vs. either aspirin or warfarin in any setting outside of orthopedics.
TOTAL: 14 STUDIES
1 Study
0 Studies
13 Studies
1 Level I
13 Level I
LITERATURE SEARCH RESULTS: A total of 14 prospectively designed, randomized controlled trials met the search criteria. LMWHs included enoxaparin, tinzaparin, dalteparin, and nadroparin. Comparator studies to these LMWHs included 9 with aspirin only, 4 with warfarin only, and 1 with both aspirin and warfarin.
Only one of these 14 studies conclusively demonstrated a benefit of an LMWH (enoxaparin), which was compared to aspirin for the prophylaxis of DVT before air travel. (Cesarone, Belcaro et al. 2002) The remainder of these studies did not demonstrate a benefit of any of the LMWH over the collective choice of either aspirin or warfarin. One study compared enoxaparin to both aspirin and warfarin individually in the oncology setting. (Palumbo, Cavo et al. 2011) In this study aspirin was comprehensively similar to enoxaparin, and warfarin produced more bleeding than enoxaparin in elderly patients only.
LMWH has produced lower rates of DVT in some studies, but the effect size is likely too small to be conclusively demonstrated in most studies. One study report claimed that the LMWH enoxaparin produced lower rates of miscarriages than did aspirin, but the report of that study has been considered to be flawed in the way of failure to present crucial baseline characteristics and other information required for a proper evaluation of the study. (Gris, Mercier et al. 2004) While warfarin was more inclined to produce bleeding than a LMWH in several studies, this finding was not shown to be statistically significant and same observation was not made with aspirin vs. LMWH.
In conclusion, the preponderance of evidence suggests a high level of evidence for a negative predictive value for improved prevention of thrombosis-related complications with any LMWH as compared with either aspirin or warfarin in nonorthopedic settings. While a comparison between aspirin and warfarin was not directly analyzed, warfarin may be more inclined than aspirin to result in bleeding complications.
LMWH VS. ASPIRIN OR WARFARIN IN NONORTHOPEDIC SETTINGS
Studies Favorable: Total 1
Level I: 1 Study
1. Venous thrombosis from air travel: the LONFLIT3 study–prevention with aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: a randomized trial.
Cesarone, M.R., et al.
Angiology, 2002. 53(1): p. 1-6.
Enoxaparin vs. aspirin vs. no prophylaxis before air travel. DVT was improved with enoxaparin.
LMWH VS. ASPIRIN OR WARFARIN IN NONORTHOPEDIC SETTINGS
Studies Unfavorable: Total 0
LMWH VS. ASPIRIN OR WARFARIN IN NONORTHOPEDIC SETTINGS
Studies Neutral: Total 13
Level I: 13 Studies
1. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages.
Dolitzky, M., et al.
Fertil Steril, 2006. 86(2): p. 362-6.
Aspirin and enoxaparin produced similar rates of miscarriages and pregnancy complications in 4 different medical centers.
2. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial.
Bath, P.M., et al.
Lancet, 2001. 358(9283): p. 702-10.
Tinzaparin vs. aspirin within 48 hours of acute ischemic stroke did not improve functional outcome. DVT rates were lower with tinzaparin but symptomatic intracranial hemorrhage was higher.
3. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial.
Berge, E., et al.
Lancet, 2000. 355(9211): p. 1205-10.
Dalteparin vs. aspirin in acute ischemic stroke or atrial fibrillation yielded comprehensively similar results.
4. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial.
Das, S.K., et al.
World J Surg, 1996. 20(5): p. 521-6; discussion 526-7.
LMWH vs. warfarin for prevention of recurrent DVT. No difference, but with trend towards LMWH. Small, open study.
5. Dalteparin versus aspirin in recent-onset branch retinal vein occlusion: a randomized clinical trial.
Farahvash, M.S., et al.
Arch Iran Med, 2008. 11(4): p. 418-22.
Dalteparin vs. aspirin in ophthalmology setting. Small study, results substantially similar.
6. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.
Gris, J.C., et al.
Blood, 2004. 103(10): p. 3695-9.
Enoxaparin vs. aspirin in the obstetric setting. Statistical data not presented, although the paper leads towards the conclusion that enoxaparin is superior to aspirin. Study design and presentation his highly flawed as described in a published critique of this paper. A few of the many omissions include failure to present baseline characteristics or method of allocation concealment.
7. Frequency of microemboli signal in stroke patients treated with low molecular weight heparin or aspirin.
Hao, Q., et al.
J Neuroimaging, 2008. 20(2): p. 118-21.
LMWH vs. aspirin in surrogate endpoint of thromosis.
8. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.
Meyer, G., et al.
Arch Intern Med, 2002. 162(15): p. 1729-35.
Enoxaparin vs. warfarin in the oncology setting. No difference in main outcome (either thrombosis or bleeding). All bleeding-related deaths, however, were in the warfarin group. Small study.
9. Low-molecular-weight heparin (nadroparin) and very low doses of warfarin in the prevention of upper extremity thrombosis in cancer patients with indwelling long-term central venous catheters: a pilot randomized trial.
Mismetti, P., et al.
Haematologica, 2003. 88(1): p. 67-73.
Nadroparin vs. warfarin in oncology setting. Comprehensively similar results. Small study.
10. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial.
Palumbo, A., et al.
J Clin Oncol, 2011. 29(8): p. 986-93.
Aspirin, warfarin, or enoxaparin in oncology setting. Comprehensively similar results with aspirin vs. enoxaparin. Warfarin was inferior to enoxaparin in elderly patients only. Aspirin was not inferior to enoxaparin.
11. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.
Pini, M., et al.
Thromb Haemost, 1994. 72(2): p. 191-7.
LMWH vs. warfarin for prevention of recurrent thrombosis. Results comprehensively similar. More cases of bleeding in the warfarin group.
12. Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study.
Strater, R., et al.
Stroke, 2001. 32(11): p. 2554-8.
Aspirin vs. LMWH in pediatric ischemic stroke patients. Comprehensively similar results.
13. Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study.
Wong, K.S., et al.
Lancet Neurol, 2007. 6(5): p. 407-13.
LMWH vs. aspirin in acute ischemic stroke. Comprehensively similar results. Large study.
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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