Irritable bowel syndrome and ischemic colitis: evidence supporting the increased use of alosetron

Alosetron, a 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist, was approved by the US Food and Drug Administration (FDA) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in women in February 2000. Initial clinical trials demonstrated significant efficacy, particularly in improving fecal urgency, stool frequency and consistency [Camilleri et al. 2001]. In a recent review and systematic meta-analysis of eight alosetron clinical trials, the number needed to treat (NNT) was reported to be 7.5 [Shah et al. 2012]. Although its efficacy was never questioned, safety became a concern as cases of ischemic colitis (IC) were reported, leading to voluntary withdrawal of alosetron by GlaxoSmithKline in November 2000. Alosetron was reintroduced in 2002 as a result of patient advocacy, with a risk management plan (RMP) designed to limit availability to women with severe IBS-D [Chang et al. 2010; Lewis, 2011].

In a comprehensive review article, Dr James Lewis presented evidence related to the association of alosetron to IC in patients with IBS in clinical trials, postmarketing experience prior to withdrawal of alosetron in November 2000, and since reintroduction in 2002. IC is the most frequently encountered form of ischemic injury of the large bowel, occurring with an incidence of 4.5–44 cases per 100,000 person-years in the general population [Higgins et al. 2004]. Two forms of IC have been described: nongangrenous and gangrenous. The majority of IC cases, that is 80–90%, are nongangrenous and reversible with or without medical therapy. The remaining 10–20% are gangrenous and tend to lead to hospitalizations, more comorbidities, and rarely surgeries [Lewis, 2011]. Dr Lewis makes the important distinction between IC and acute mesenteric ischemia and chronic mesenteric ischemia. Both acute mesenteric ischemia and chronic mesenteric ischemia are associated with serious morbidities and high mortality. Only IC, not acute mesenteric ischemia or chronic mesenteric ischemia, has been associated with 5-HT₃ receptor antagonists [Lewis, 2011].

Some factors reported to increase the risk of IC include genetics, strenuous exercise, illicit drugs such as cocaine, and pharmaceutical agents including triptans, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, opioids, female hormonal therapy, antidiarrheal medications, and constipation-causing drugs [Cappell, 2004; Hass et al. 2007; Longstreth and Yao, 2009, 2010; Theodoropoulou and Koutroubakis, 2008]. Furthermore, certain medical conditions increase the risk of IC, including congestive heart failure, hypertension, atrial fibrillation, rheumatoid arthritis, chronic obstructive pulmonary disease, diabetes mellitus, diarrhea, and IBS [Longstreth and Yao, 2010]. Dr Lewis provides an in-depth review of the epidemiological evidence, gathered over the past decade, supporting an association between IBS and IC [Lewis, 2011]. This evidence is in the form of real-world, population-based, case–control studies from hospitalized patients or retrospective analyses of medical claims databases using International Classification of Diseases, ninth revision coding, or medical file review [Chang et al. 2008; Cole et al. 2004; Hervé et al. 2009; Singh et al. 2004; Suh et al. 2007]. These data suggest that the background incidence of IC is greater in patients with IBS treated with medications other than alosetron compared with subjects without IBS [Lewis, 2011]. A population-based study using medical claims data from a large US health maintenance organization reported that the risk of IC was increased by three- to fourfold in patients with IBS versus those without IBS, with an overall relative risk of 3.39 [Cole et al. 2004]. Other epidemiological studies also support this association with a relative risk of IC in IBS versus controls ranging from 3.17 to 8.16 [Cziraky et al. 2006; Suh et al. 2007]. These studies robustly and consistently demonstrate evidence of a higher prevalence of IC in patients with IBS who have not been treated with 5-HT₃ antagonists. Despite identifying a number of factors and conditions, the precise pathophysiology of IC remains unknown, although it appears to be linked to factors affecting blood supply to the intestine. However, the role of serotonin and 5-HT₃ receptors in this process remains unclear.

Dr Lewis reviewed the results of analyses of IC cases in patients with IBS associated with alosetron use prior to its withdrawal in November 2000 and after its reintroduction in 2002 [Lewis, 2011]. Pooled data from initial trials and the postmarketing period in 2000 revealed a significant increase in the rate of IC in alosetron-treated patients compared with placebo (0.14% versus 0.0%, p = 0.03) [Chang et al. 2006]. IC in all cases was transient, reversible, and resolved without long-term consequences [Chang et al. 2006]. Since reintroduction of alosetron under a risk management plan in 2002, cases of IC have been rare and stable (0.95 cases per 1000 patient-years) as detailed in an analysis of postmarketing data from November 2002 to June 2008 by Chang and colleagues [Chang et al. 2010] These incidence rates were similar to those reported in postmarketing before withdrawal [Chang et al. 2010]. Furthermore, since the reintroduction of alosetron there continues to be no reported deaths associated with IC, as was the case prior to reintroduction [Chang et al. 2010]. Overall, in alosetron clinical trials the cumulative incidence of IC was reported to be 0.2% after 3 months and 0.3% after 6 months of treatment with alosetron, with a single case of IC reported in a patient receiving placebo [Prometheus Laboratories, 2010].

Cilansetron, another 5-HT₃ receptor antagonist, was associated with eight suspected cases of IC with a rate of 3.77 cases per 1000 patient-years [Chey and Cash, 2005]. This medication received a ‘nonapprovable’ letter from the FDA in 2005 and its development was suspended [Stacher, 2007]. Renzapride, a mixed 5-HT₄ receptor agonist and 5-HT₃ receptor antagonist, studied in IBS with constipation was found to be associated with IC; three cases out of 971 patients were reported during a 1-year study [Lembo et al. 2010]. Lastly, tegaserod, a partial 5-HT₄ receptor agonist, approved by the FDA in 2002 for treatment of IBS with constipation in women, was not found to be associated with IC in the initial clinical trials [Müller-Lissner et al. 2006; Pfannkuche et al. 1995]. Postmarketing cases of IC were reported in patients with comorbidities or medication usage likely to increase risk of IC; however, these rates were probably similar to those in the general population. In 2007, tegaserod was eventually withdrawn after a pooled analysis suggested an 11-fold increase (versus placebo) in the risk of cardiovascular events [Lewis, 2011].

Dr Lewis’s review of the data over the past decade shows that the risk of IC associated with alosetron treatment remains low, and it is uncertain if the observed rates of IC reflect other factors such as the background rate inherent with IBS-D or an antidiarrheal effect [Lewis, 2011]. In addition, incidence of complications of constipation (CoC) including fecal impactions and ileus has been reduced to even lower levels over the past decade [Chang et al. 2010]. A recent review and systematic meta-analysis of clinical trials reported the number needed to harm (NNH) was 19.4 for alosetron, similar to tricyclic antidepressants with an NNH of 18.3 [Shah et al. 2012]. Furthermore, patient surveys and studies evaluating the RMP for alosetron reveal that patient and healthcare provider adherence and compliance with the various elements of the RMP has been high and mitigation of serious outcomes associated with IC and CoC has been effective [Chang et al. 2010; Miller et al. 2006]. In the most recent study by Nicandro and colleagues, it was demonstrated that alosetron has been and continues to be used effectively and safely under the RMP, and appears to provide long-term benefit to appropriate patients with IBS-D [Nicandro et al. 2012].

The misconception that alosetron is associated with high rates of IC, however, persists in the medical community. One of the unintended consequences of the risk management plan is that physicians appear to reserve the use of alosetron for ultra-severe cases of IBS-D [Miller et al. 2006; Nicandro et al. 2012]. As there are no standard criteria to judge severity of IBS, the FDA-approved prescribing information for alosetron recommends that at least one of the following severity criteria is present: frequent and severe abdominal pain/discomfort; fecal urgency or fecal incontinence; or restriction in daily activities due to IBS [Nicandro et al. 2012]. Many clinicians tend to be overly conservative in prescribing alosetron by unnecessarily requiring the presence of all three severity criteria, thereby making it unavailable as a treatment option to many patients who would benefit.

From the perspective of the patient with IBS, due to the limited therapeutic options available to them, many are willing to accept considerable risk of side effects for the possibility of receiving an efficacious treatment [Lacy et al. 2009]. An online study conducted by the International Foundation for Functional Gastrointestinal Disorders in collaboration with the University of North Carolina Center for Functional GI and Motility Disorders found that patients with IBS would give up 25% of their remaining life (average 15 years), and 14% of patients would accept a 1 in 1000 chance of death to be symptom free [Drossman et al. 2009]. Significantly, alosetron has also been reported to improve measures of patient-reported quality of life and workplace productivity in patients with IBS-D [Jhingran et al. 2001; Watson et al. 2001].

In summary, extensive data from alosetron clinical trials and postmarketing experience has shown: no increase in rates of IC, as feared in 2000, which remain consistently rare and stable over time; no deaths due to IC since reintroduction of alosetron in 2002; the risk management plan for alosetron having a high degree of compliance and effectiveness in mitigating IC and CoC; patients with IBS appear to be predisposed to developing IC with up to an eightfold increase in risk as demonstrated by epidemiological evidence; and patients with severe IBS-D are willing to accept some risks of side effects for a better quality of life [Lacy et al. 2009].

Given this evidence, the time may have come to consider use of alosetron in appropriate IBS-D patients who are otherwise not prescribed the medication because of excessive fear of IC. Physicians and patients accept the risks of using a wide range of medications such as NSAIDs or sildenafil (Viagra, Pfizer Lab) that are associated with a variety of serious side effects, including cardiovascular adverse events (i.e. myocardial infarction, stroke, ventricular arrhythmia, or death from coronary heart disease) in order to treat non-life-threatening conditions. I believe patients with IBS deserve the same choice.