AFP Journal Club
The Story Behind the Study
Is Unfractionated Heparin Equivalent to Low-Molecular-Weight Heparin for Venous Thromboembolism?
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Am Fam Physician. 2008 Jun 1;77(11):1492-1493.
Each month, our three presenters will review an interesting journal article in a conversational manner. These articles will involve “hot topics” that affect family physicians or will “bust” commonly held medical myths. The presenters will give their opinions about the clinical value of the studies discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP.
This Month's Article
Kearon C, Ginsberg JS, Julian JA, et al., for the Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006;296(8):935–942.
Is weight-based unfractionated heparin as good as weight-based low-molecular-weight heparin for outpatient treatment of venous thromboembolism (without checking and adjusting for partial thromboplastin time)?
Mark: For a number of years, we have been using low-molecular-weight heparin (LMWH; e.g., enoxaparin [Lovenox]) for the outpatient treatment of venous thromboembolism. The big advantage of LMWH is that you do not have to check partial thromboplastin time (PTT) and that it can be given as an outpatient treatment. What if we could do exactly the same thing with unfractionated heparin, which is a fraction of the cost of LMWH?
What does this article say?
Mark: This was a randomized, open-label, adjudicator-blinded, noninferiority trial of weight-based dalteparin (Fragmin) or enoxaparin at a dosage of 100 IU per kg subcutaneously every 12 hours versus weight-based unfractionated heparin at a dosage of 333 U per kg followed by 250 U per kg subcutaneously every 12 hours. Adjudicator-blinded means that the folks assessing the clinical outcomes (e.g., recurrent thromboembolism, death) were blinded to treatment assignment, but patients and their physicians were not. The trial included 708 adults with acute venous thromboembolism. Patients had to be older than 18 years, have new deep venous thrombosis or pulmonary embolism, and have no contraindications to heparin.
All patients received the study drugs as outpatients. The investigators did not check PTTs and did not adjust the dosage of unfractionated heparin. What they found was that the unfractionated heparin was just as good as LMWH. So according to this study, we can use subcutaneous unfractionated heparin in outpatients with new deep venous thrombosis or pulmonary embolism.
Should we believe this study?
Mark: Sort of. The authors did a couple of things that were a bit odd. They started off okay by doing a power analysis that calculated that they needed to include 824 patients to prove that these two therapies are equivalent. A power analysis is done to make sure there are enough patients in a study to show a difference (if there is one). Not having enough patients to show a difference is called a type II error.
So what did the study authors do then? They stopped recruiting when they reached 708 patients because “a blinded interim analysis revealed a lower-than-expected frequency of recurrent venous thromboembolism in all randomized patients.” Huh? This is exactly the wrong thing to do! If fewer people have an event, you need to enroll more (not fewer) patients to see if the therapies are equivalent. For example, if no patients had an MI in a study of MIs, you would want to increase the number of participants until there were an adequate number of MIs in each group. Otherwise, your study would be worthless.
Bob: Because they stopped enrollment early, this study wasn't powered to demonstrate equivalence or the superiority of one treatment versus the other. Nor was it powered to detect a difference in adverse outcomes. So we can't say that one drug has more adverse outcomes than the other. However, there was a trend toward increased rates of death and bleeding at 90 days in the group given LMWH. But is this a real difference? This is where post-marketing studies come into play. Many adverse effects are not apparent or do not reach statistical significance in small studies. Once a drug is given to thousands of people, the side effect profile becomes clearer. A good example of this is cerivastatin (Baycol). It is now off the U.S. market because postmarketing surveillance found that it was associated with liver failure.
What should the family physician do?
Andrea: Although the study was underpowered to demonstrate equivalence between unfractionated heparin and LMWH, it is likely that they are equivalent in terms of treating venous thromboembolism. There may be more bleeding with LMWH, but again, the study was not powered to find this difference.
Mark: It is unfortunate that they did not enroll enough patients. There could be a major monetary saving if the standard of care was to use unfractionated heparin in outpatients. According to pricing on http://www.drugstore.com, a single dose of unfractionated heparin for a 154-lb (70-kg) patient costs approximately $4, and a single dose of enoxaparin for a 154-lb patient costs approximately $50. That comes to approximately $8 for a single day of therapy with unfractionated heparin versus $100 per day with LMWH.
Bob: I feel very comfortable recommending subcutaneous unfractionated heparin as a treatment for patients with acute venous thromboembolism. Previous studies have demonstrated that appropriately dosed subcutaneous heparin is more effective and produces less bleeding than continuous intravenous heparin in patients with deep venous thrombosis.1 And a 2004 Italian study of 720 patients with venous thromboembolism noted no difference in outcomes between patients randomized to subcutaneous unfractionated heparin or LMWH (nadroparin; not available in the United States).2 However, isn't it sad that this therapy (unfractionated heparin), which appears to be as good as (if not better than) the more expensive LMWH, will not be promoted or advertised in any fashion?
Unfractionated heparin given subcutaneously is likely just as effective as low-molecular-weight heparin for the outpatient treatment of venous thromboembolism, and you don't have to check partial thromboplastin time.
Even though this study was underpowered to prove equivalence, treatment with subcutaneous unfractionated heparin is a viable option, especially when access to medication is limited because of cost.
A type II error occurs when a study is too small to find a real difference between two treatments.
When you have fewer events in a study than you expect, you need to increase the number of participants, not decrease it (as was done in this study).
Post marketing monitoring is often required to find a difference in adverse outcomes that are associated with the drugs.
Address correspondence to Mark A. Graber, MD, at email@example.com. Reprints are not available from the authors.
Author disclosure: Nothing to disclose.
coming next month: American Lung Association Asthma Clinical Research Centers, Peters SP, Anthonisen N, et al. Randomized comparison of strategies for reducing treatment in mild persistent asthma [published correction appears in N Engl J Med. 2007;357(7):728]. N Engl J Med. 2007;356(20):2027–2039.
1. Hommes DW, Bura A, Mazzolai L, Büller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta-analysis. Ann Intern Med. 1992;116(4):279–284.
2. Prandoni P, Carnovali M, Marchiori A, for the Galilei Investigators. Subcutaneous adjusted-dose unfractionated heparin vs. fixed-dose low-molecular weight heparin in the initial treatment of venous thromboembolism. Arch Intern Med. 2004;164(10):1077–1083.
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