Cochrane for Clinicians

Putting Evidence into Practice

Tegaserod in Patients with Irritable Bowel Syndrome

MICHAEL SCHOOFF, M.D., and CASEY STELTER, M.D., Clarkson Family Medicine Residency Program, Omaha, Nebraska

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/cochrane/revabstr/AB003960.htm.

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Michael Schooff, M.D., and Casey Stelter, M.D., present a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

Clinical Scenario

A 35-year-old woman presents with recurrent episodes of abdominal pain, constipation, and a sense of incomplete emptying after defecation. She has a history of irritable bowel syndrome (IBS).

Clinical Question

In patients with IBS, is tegaserod an appropriate therapy for treatment of abdominal pain and general dissatisfaction with bowel habits?

Cochrane Abstract Background. IBS is a complex disorder that encompasses a wide profile of symptoms. Current drug treatments for IBS are of limited value, and many treatments target specific symptoms. Tegaserod, a 5-HT4 receptor partial agonist, has a novel mechanism of action in the treatment of IBS. Objectives. The objective of this review1 was to evaluate the efficacy and tolerability of tegaserod in the treatment of IBS in patients 12 years of age and older. Search Strategy. The authors searched MEDLINE (1966 to November 2002) and EMBASE (1980 to November 2002) using the key words "tegaserod," "HTF 919," "irritable bowel," and "colonic diseases, functional." The Cochrane Central Register of Controlled Trials, the Inflammatory Bowel Disease Review Group Specialized Trials Register, and Science Citation Index also were searched. Proceedings from the British Society of Gastroenterology Annual Meeting, and Digestive Disease Week (1998 to 2002) were searched by hand. Reference lists from relevant articles were reviewed. The manufacturer of tegaserod was contacted. Selection Criteria. Randomized or quasi-randomized controlled trials that focused on clinical end points and compared tegaserod with placebo, no treatment, or any other intervention (pharmacologic or nonpharmacologic) in patients 12 years and older who had been diagnosed with IBS were considered for review. Data Collection and Analysis. Study inclusion and exclusion, data extraction, and quality assessment were performed independently by two reviewers. Meta-analysis was performed when study populations, designs, outcomes, and statistical reporting allowed the valid combination of data. Eight short-term, placebo-controlled studies fulfilled the inclusion criteria. These studies were conducted predominantly in women. Seven studies evaluated the efficacy of tegaserod on global GI symptoms in patients with constipation-predominant IBS. One small study evaluated safety in patients with diarrhea-predominant IBS. Primary Results. Compared with patients who received placebo, the relative risk (RR) of responding in terms of global relief of GI symptoms was significantly higher in patients who received tegaserod in dosages of 12 mg per day (RR, 1.19; 95 percent confidence interval [CI], 1.09 to 1.29) and 4 mg per day (RR, 1.15; 95 percent CI, 1.02 to 1.31), with numbers needed to treat (NNT) of 14 and 20, respectively. When patients who received tegaserod at any dosage (n = 4,040) were compared with patients who received placebo, the RR of responding was 1.17 (95 percent CI, 1.08 to 1.27), with an NNT of 17. Although the pooled results indicate a statistically significant benefit with tegaserod, the a priori minimal clinically important differences that were set in two of the four pooled studies were not reached. Tegaserod did not significantly improve patients' individual symptoms of abdominal pain and discomfort, although a statistically significant improvement in bowel habits was noted in patients in the lower dosage group. There was a nonsignificant trend in favor of the 12-mg dosage. When GI symptoms were assessed separately, symptoms indicative of GI motility, such as number of bowel movements and days without bowel movements, generally were improved in patients who received tegaserod, although the proportion of patients experiencing diarrhea was significantly higher in the 12-mg group than in the placebo group (RR, 2.75; 95 percent CI, 1.90 to 3.97), with a number needed to harm (NNH) of 20. The effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies. Reviewers' Conclusions. Tegaserod appears to improve the overall symptomatology of IBS, but there are few data on its effect on quality of life. More information is needed about its efficacy in men. It also would be of interest to know whether treatment with tegaserod leads-directly or indirectly-to changes in visceral sensitivity or psychopathology, which are considered important in the pathophysiology of this condition. These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Evidence-Based Answer

Tegaserod offers modest improvement in global gastrointestinal (GI) symptoms in women with constipation-predominant IBS, without having significant effect on symptoms of abdominal pain and discomfort.

Practice Pointers

IBS is a chronic, relapsing condition encompassing a wide variety of GI symptoms, including abdominal pain and altered bowel habits. The condition affects 10 to 15 percent of the North American population and is twice as common in women as in men.2 The etiology is unknown, although motility disorders, visceral hypersensitivity, and sensitization of the central nervous system have been implicated. IBS is a clinical diagnosis of exclusion, and traditional treatments, such as bulking agents, anticholinergics, antispasmodics, antidiarrheals, and antidepressants, have targeted individual symptoms. Tegaserod, which stimulates smooth muscle within the GI tract and increases peristalsis and gut transit time, offers a new treatment option for the global symptoms of IBS.

Tegaserod in dosages of 12 mg daily has shown statistical significance in two studies, and a nonsignificant but beneficial trend in two additional randomized controlled studies, in the reduction of global GI symptoms. These self-reported subjective assessments asked patients to compare their GI symptoms before entering the trial with symptoms after initiating therapy. Patients in both treatment groups reported complete or considerable relief in GI symptoms.

Abdominal pain symptoms did not appear to be altered significantly, although beneficial trends were noted in some patients in both treatment groups. Patient satisfaction with bowel habits suggests that the lower dosage may be more efficacious, although a similar trend in patient satisfaction was noted in the higher dosage group.

Stool frequency and the number of days without bowel movements improved in patients in the 12-mg group. In one study, subjective scores of bloating, straining, and stool consistency decreased and stool frequency increased in the higher dosage group. However, these results were not consistent across all studies.

Tegaserod was well tolerated by most patients. The most common side effect was diarrhea, which was experienced significantly more often by patients in the higher dosage group (NNH, 20). Headache, abdominal pain, and nausea were experienced with increased frequency in this group as well, but this trend did not reach statistical significance. Cardiac effects were not apparent with this agent as they are with other partial 5-HT4 receptor agonist GI-motility agents such as cisapride. Three studies investigated the potential effect of QTc interval prolongation but did not identify an increase in frequency of ECG abnormalities between the high-dosage, low-dosage, and placebo groups.

Few data about tegaserod's efficacy in men and its impact on quality of life exist. Longer-term studies are needed to determine the duration of treatment and the safety of this agent with prolonged use. Tegaserod appears to be an option for short-term relief of global GI symptoms in women with constipation-predominant IBS, but it does not affect their abdominal pain and discomfort.

The Authors

MICHAEL SCHOOFF, M.D., is associate director of the Clarkson Family Medicine Residency Program in Omaha. He received his medical degree from the Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, Md., and completed a family practice residency at Womack Army Medical Center, Fort Bragg, N.C.

CASEY STELTER, M.D., is a third-year family medicine resident at the Clarkson Family Medicine Residency Program in Omaha. He received his medical degree from the University of Utah School of Medicine, Salt Lake City.

Address correspondence to Michael Schooff, M.D., Clarkson Family Medicine, 4200 Douglas St., Omaha, NE 68131 (e-mail: mschooff@nebraskamed.com). Reprints are not available from the authors.

REFERENCES

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Cochrane Briefs

Calcium and Prevention of Colorectal Cancer

Clinical Question

Do calcium supplements prevent colorectal cancer and adenomatous polyps?

Evidence-Based Answer

Combined evidence from two clinical trials of calcium supplementation lasting for several years revealed a reduced rate of recurrent colorectal adenoma. However, evidence is insufficient to recommend supplementation with dietary calcium for patients who have never had an adenoma.

Practice Pointers

A recent review1 of epidemiologic evidence did not show that calcium supplementation prevents colon cancer. However, epidemiologic studies of dietary interventions for cancer prevention are vulnerable to survivor bias, confounding factors, and inaccurate dietary recall.

Weingarten and colleagues reviewed the literature to find randomized controlled trials (RCTs) of calcium supplementation used for prevention of colon cancer. Such studies are difficult because they require a large number of patients for a long time. Weingarten found two studies that included a total of 1,346 patients with a previous diagnosis of colon adenoma. In one study, patients took 1,200 mg of calcium daily for four years. Patients in the other study took 2,000 mg per day for three years. When data from the studies were combined, there was a 26 percent relative reduction in recurrent adenomas (odds ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). However, there were not enough new diagnoses of colon cancer to support conclusions about calcium supplementation's effect on cancer prevention. No RCTs were found that studied calcium supplementation for primary cancer prevention in patients who had never had a polyp or tumor.

Dietary calcium supplementation promises to reduce the risk of colon cancer
moderately. Although it would be appealing to find a simple, inexpensive, and safe dietary supplement to prevent colon cancer, comprehensive programs for healthy living are more likely to be effective. For prevention of colon cancer, the American Cancer Society recommends increasing the intensity and duration of physical activity; eating more vegetables and fruits; limiting intake of red meat; avoiding obesity; and avoiding excess alcohol consumption.2

CLARISSA KRIPKE, M.D.

Weingarten MA, et al. Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps. Cochrane Database Syst Rev 2004;(3):CD003548.

REFERENCES

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Link Between Metformin and Lactic Acidosis?

Clinical Question

Does metformin cause lactic acidosis?

Evidence-Based Answer

There is no evidence that metformin causes lactic acidosis, even in patients with renal insufficiency or other comorbidities. Although caution is still indicated in patients with multiple or severe comorbidities, it appears that the initial concern about lactic acidosis with this drug was misplaced.

Practice Pointers

Unlike other agents used in the treatment of type 2 diabetes mellitus, metformin has been shown to reduce mortality in obese patients.1 It is therefore being used increasingly often for the treatment of type 2 diabetes. However, many physicians are concerned about a possible increase in the risk of lactic acidosis, particularly in patients who have cardiovascular disease, renal disease, liver problems, chronic respiratory disease, or advanced age. Phenformin, another biguanide, was withdrawn from the market after a rate of 40 to 64 cases of lactic acidosis per 100,000 patient-years was reported.

Salpeter and colleagues found 176 studies that met their inclusion criteria, of which 118 were prospective clinical trials. The 176 studies followed 26,099 patients who took metformin for a total of 65,621 patient-years, and 8,943 control patients who did not take metformin for 30,002 patient-years.

Although many studies excluded patients with comorbidities, a significant number did not. For example, 81 did not exclude patients with renal insufficiency. Remarkably, there was not a single case of fatal or nonfatal lactic acidosis in any of the patients, whether or not they took metformin. Therefore, the upper limit of a 95 percent confidence interval with zero at the lower end is 8.4 cases per 100,000 patient-years in patients taking metformin and 9.0 cases per 100,000 patient-years in patients not taking it. There was no difference in intermediate physiologic outcomes, such as change in lactate levels, and no evidence of publication bias. The authors cite data showing that contraindications to the use of metformin are largely ignored in clinical practice. It appears that, in this case, physicians are correct.

MARK EBELL, M.D., M.S.

Salpeter S, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2004;(3):CD002967.

REFERENCES

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