I have reported previously on the use of heparin
in Ulcerative Colitis. A trial of heparin versus placebo was
recently done. The study was organized by Dr. Korzenik, now at Washington
University School of Medicine in St. Louis, MO. I ran one of the
sites that participated in the study. The results of the study were
eagerly awaited. The results of the trial were recently reported
at a session of Digestive Disease Week, a major international meeting that
I attended in Orlando, Florida. Following is the abstract as published,
with notes afterwards that I added. The short answer is that it works.
Read on for details.
AGA Research Forum G3264 #3046
A multi-center, Randomized, Controlled Trial of Heparin for the Treatment of Ulcerative Colitis
J R Korzenik, Washington Univ Sch of Medicine, St. Louis, MO; Marie E Robert, Yale Univ Sch of Medicine; Alain Bitton, Royal Victoria Hosp; Malcom Robinson, Oklahoma Fdn for Digest Res; Ellen J Scherl, Royal Victorian Hosp; Rosemarie L Fisher, Henry J Binder, Yale Univ Sch of Medicine
Background: A series of open-labeled trials suggest a benefit of heparin for the treatment of Inflammatory Bowel Disease (IBD). No prospective randomized controlled trials have been performed. We report the initial data obtained from a large multicenter controlled trial of heparin therapy for the treatment of moderate to sever ulcerative colitis (UC). Aims: To assess safety and efficacy of heparin in the treatment of active UC. Methods: Subjects were enrolled with moderate to severe ulcerative colitis having four or more stools/day. Permissible concomitant medications included mesalamine, steroids and azathioprine/6-MP for specified durations prior to enrollment. Subjects were randomized (1:1) to saline injections or standard porcine heparin injections at 10,000 units subcutaneously (sq) bid for 6 weeks. In those randomized to heparin, the dose was adjusted by an unblinded observer to 10,000 units sq tid for patients whose appt remained below the upper limit of normal. A subgroup (20%) of subjects randomized to placebo received tid saline injections. Randomization was stratified by extent of colitis (left sided vs pan - colitis) and by use of steroids. Patients were monitored with weekly aPTT and twice weekly CBC. Efficacy was determined by clinical assessment of stool frequency, frequency of bloody stools, patient global scale, physician global scale, sigmoidoscopic and histologic assessment (at week 0 and end of week 6). Failure was established by an increase in existing medications or need for additional medication. Decrease of hematocrit by 6 points or decrease of platelets below 100,000 was also criteria for discontinuation. Results: 70 subjects were enrolled at 9 sites. No severe adverse effects were observed in any subject. One subject was prematurely discontinued because of a decrease in hct of > 6 points but was in remission at the time with no evidence of bleeding. Three patients noted a transient increase in rectal bleeding though not clinically significant and were able to continue their involvement. One patient developed a psoriasiform rash at the injection sites. Enrollment has been completed, but the trial has not yet been unblinded. Conclusions: 1) The use of heparin is safe in the setting of moderate to severe ulcerative colitis. 2) Several subjects are completing their involvement at this time. Data for clinical efficacy will be reported after the trial is unblinded and will be available shortly.
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At the conference the results were further detailed. The major result was that the remission rate was 42% for patients on heparin, 20% for control patients. It should be noted that these patients were all not responding to regular therapy, so heparin was started only late in the course of their UC flare. There was no significant increase in bleeding rates. Patients that did respond all started to respond by three weeks. One issue that was discussed was that the heparin was given subcutaneously rather than intravaneously. This was done because it was an outpatient study. Since heparin given subcutaneously may make different fractions of the heparin available differentially, it is possible that IV use is more effective. Note, also, the placebo response rate. 20% is somewhat low for a placebo response rate, showing that these were chronically ill patients. Nonetheless, 20% of patients did go into remission with just another month of their treatment without heparin. This shows the importance of a placebo controlled trial. Had the control group not been included a result of just 40% response might have been believed to be placebo alone. The placebo group shows that the response was real.
The information here is from an oral presentation. These results have not been published in a journal and have not been carefully reviewed by outside experts. A number of the results described in preliminary form do not turn out to be true. The usefullness of a preliminary report is for early distribution of results and for feedback to the author before publication. Due care needs to be exercised when acting on preliminary results.
Stephen Holland, M.D.