Kelly Chong

Evaluation of Harm in the Pharmacotherapy of Irritable Bowel Syndrome

OBJECTIVE Current treatment options for irritable bowel syndrome are limited and often poorly studied. A select few drugs have been studied in irritable bowel syndrome, and the number needed to treat is frequently used to assess the relative efficacy of these treatments. However, side effects are an important consideration in the clinical decision on which particular treatment to use. This study examines trials of subjects with irritable bowel syndrome with diarrhea and constipation who are receiving a drug intervention deemed of merit by the American College of Gastroenterology task force and compares these therapies to examine the number needed to harm using a systematic review and meta-analysis approach. METHODS Potential studies of irritable bowel syndrome treatments were identified through a search of MEDLINE (1950 to April 2011), EMBASE (1980 to April 2011), the Cochrane central register of controlled trials, and the bibliography of recent meta-analyses. Clinical trials of pharmacotherapy for irritable bowel syndrome were eligible for inclusion only if a description of adverse events and the number of patients who discontinued treatment because of adverse events were reported. The relative risk of experiencing an adverse event requiring discontinuation of treatment was used to determine the number needed to harm. In addition, the number and severity of adverse events were summarized. RESULTS Twenty-six clinical trials (4 with selective serotonin reuptake inhibitors, 3 with lubiprostone, 6 with tricyclic antidepressants, 8 with alosetron, and 5 with rifaximin) were included. Lubiprostone was safe with insignificant harm in one combined phase III trial. Selective serotonin reuptake inhibitors did not have enough data for a reliable meta-analysis of harm but seemed to be safe. More rigorous data were available for tricyclic antidepressants, alosetron, and rifaximin; the numbers needed to harm were 18.3, 19.4, and 8971, respectively, and the numbers needed to treat were 8, 7.5, and 10.6, respectively. For tricyclic antidepressant and alosetron, an adverse event resulting in discontinuation of the study medication occurred for every 2.3 and 2.6 patients who benefited from a drug, respectively. For rifaximin, this number was 846 patients. In addition, adverse events were more common with tricyclic antidepressants and alosetron. CONCLUSION In irritable bowel syndrome with diarrhea, tricyclic antidepressants and alosetron are associated with a significant number needed to harm compared with rifaximin. Apart from lubiprostone, treatment of irritable bowel syndrome with constipation is limited to small studies (with poor descriptions of side effects), although lubiprostone and selective serotonin reuptake inhibitors appear safe.

History of tonsillectomy is associated with irritable bowel syndrome.

To the Editor: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by altered bowel function, abdominal discomfort, and bloating affecting 20% of individuals worldwide. The diagnosis is based on specific clinical criteria in the absence of a detectable organic cause. Interestingly, there is growing literature that patients with IBS have alterations in intestinal microbiota. The human gut is an elaborate ecosystem composed of 10 bacteria established in the first year of life and continuously altered by exogenous factors; however, genetics significantly contribute as well. The general requirement of intestinal colonization is microbial access to the intestinal tract, counteracted by enzymes, gastric acid, and the mucosal immune system. As microbes enter the human digestive tract, the first major encounter with the host immune system is the tonsils. The tonsils are important sentinels in the detection of foreign antigens/bacteria entering the digestive tract, and their removal may influence bacterial colonization/invasion of the alimentary tract. We examined whether a history of tonsillectomy is associated with the presence of IBS. We utilized a prospectively collected dataset of patients referred to a tertiary medical center. Patients with IBS (Rome I criteria) completed a symptom questionnaire to assess bowel symptoms. Bivariate and multivariate analyses were employed to assess associations between IBS, tonsillectomy, GI symptoms, and demographics. A total of 1125 patients (72% female), mean age 44.4±17.5 years were evaluated. Of these, 530 patients had IBS. A history of tonsillectomy was observed in 59.5% and 40.5% of patients with and without IBS, respectively (P=0.001). Confounding variables associated with IBS included age and sex; after controlling for age and sex, tonsillectomy was significantly associated with IBS (P=0.001). This is the first study demonstrating that tonsillectomy is associated with IBS. The rationale for this relationship is unclear, although we have set forth several hypotheses: the health seeking nature of IBS patients and higher rates of other surgeries may explain the higher rate of tonsillectomy, inflammation of the tonsils. Furthermore, the need for tonsillectomy implies an alteration in the host immune response (also found in IBS patients), and the absence of tonsils may enable successful and undetected pathogen penetration into the intestinal tract leading to postinfectious IBS or even bacterial overgrowth. Further investigation is warranted to understand the novel link between tonsillectomy and IBS.

Evaluating Study Withdrawal Among Biologics and Immunomodulators in Treating Ulcerative Colitis: A Meta-analysis of Controlled Clinical Trials.

Background:We conducted a systematic review and meta-analysis to evaluate the efficacy and adverse event (AE)-associated tolerability of treatment with immunomodulators and biologics in ulcerative colitis clinical trials. Methods:We performed a literature search of PubMed and the Cochrane databases to identify randomized placebo-controlled trials of immunomodulators and biologics. Tolerability was defined through study withdrawal due to AEs and efficacy through clinical response in induction trials and clinical remission in maintenance trials. We performed meta-analyses using a random-effects model to determine relative risks (RRs) of efficacy and study withdrawal. Number needed to treat (NNT) and number needed to stop (NNS) were determined. The ratio of NNS/NNT was calculated, with a higher ratio indicating a greater number of patients in remission for every AE study discontinuation. Results:We examined 13 single-agent trials representing biologics (infliximab, adalimumab, golimumab, and vedolizumab) and immunomodulators (tacrolimus and azathioprine). Induction therapy did not result in excess study withdrawal with immunomodulators (RR = 0.9, 95% CI 0.1–12.0) or biologics (RR = 0.7, 95% CI 0.3–1.8), therefore the NNS/NNT ratio could not be assessed because of high tolerability. Maintenance immunomodulator therapy resulted in a NNS of 14 (RR = 2.8, 95% CI 0.7–10.5) and NNS/NNT ratio of 2.4 in 2 trials. Biologics did not result in excess study withdrawal in maintenance (RR = 0.7, 95% CI 0.3–1.7) or combined induction-and-maintenance (RR = 0.6, 95% CI 0.4–1.0) trials. Conclusions:Biologics were not associated with a higher RR of study withdrawal due to AE than placebo. There were insufficient data to compare these results with immunomodulators.

Low serum sodium levels at hospital admission: Outcomes among 2.3 million hospitalized patients

Background Hyponatremia is the most common electrolyte disorder among hospitalized patients. Controversies still exist over the relationship between hyponatremia and outcomes of hospitalized patients. Methods To analyze the association of low serum sodium levels at hospital admission with in-hospital mortality and patient disposition and to compare the distribution of the risk of death associated with hyponatremia across the lifespan of hospitalized patients, we conducted an observational study of 2.3 million patients using data extracted from the Cerner Health Facts database between 2000 and 2014. Logistic regression models were used in the analyses. Results At hospital admission 14.4% of hospitalized patients had serum sodium levels [Na] <135 mEq/L. In adjusted multinomial logistic regression analysis, we found that the risk of in-hospital mortality significantly increases for [Na] levels < 135 or ≥143 to ≤145 mEq/L compared to the reference interval of 140 to <143 mEq/L (p<0.001). We observed similar trends for the relationship between [Na] levels and discharge to hospice or to a nursing facility. We demonstrated that younger age groups (18 to <45, 45 to <65) had a higher risk of in-hospital mortality compared to older age groups (65 to <75, ≥75) for [Na] levels <130 mEq/L or 143 to ≤145 mEq/L (p<0.001). Conclusions Hyponatremia is common among hospitalized patients and is significantly associated with in-hospital mortality, discharge to hospice or to a nursing facility. The risk of death and other outcomes was more evident for [Na] <135 mEq/L. The mortality associated with low [Na] was significantly higher in younger versus older patients.

5 The Comparative Effectiveness of Biologics and Immunomodulators for the Treatment of Ulcerative Colitis

G A A b st ra ct s The time horizon was one year. Transition probabilities were derived from published controlled trials and observational studies (SONIC, GAIN, CHARM). Age-specific NHL incidence and mortality rates were derived from the SEER registry. The hazard ratio of NHL from AZA exposure was derived fromCESAME (HR 5.28 vs.1 for IFXmonotherapy). The incidence of HSTCL with AZA use was incorporated in a model examining 25-yo males, and was estimated from two population-based cohorts assessing the incidence of this usually fatal malignancy (baseline incidence 11.2/100,000 person-years). Secondary analyses accounted for life expectancy beyond the time horizon. Expected values and incremental effectiveness were calculated for patients initiating therapy across a range of ages from 25 to 75, and reported in quality-adjusted life years (QALYs). Deterministic and probabilistic analyses were conducted. Markov cohort analysis of 1 million individuals was performed. RESULTS: Combination therapy was the preferred strategy in the baseline case (0.7714 vs. 0.7611 QALYs). Combination therapy resulted in fewer surgeries (94,888 vs. 144,351), deaths (4133 vs. 4155), and patients with active disease (162,524 vs. 198,191). This benefit persisted across all ages in the base model, though the margin of benefit decreased with increasing age (FIGURE 1). When accounting for life years lost due to mortality, monotherapy was preferred if the HR of NHL with AZA therapy was >11.5 in those age 65 or >6.9 in those age 75 (FIGURE 2). These values are within the 95% CI of the HR reported in CESAME (HR 5.28, 95% CI 2.01 13.9). For 25-yo males, accounting for the risk of HSTCL, monotherapy resulted in fewer deaths and was the preferred strategy if the incidence of HSTCL was greater than 24 per 100,000. CONCLUSION: For individuals from ages 35 to 65, combination therapy is the preferred strategy. However, for those who are >65, and particularly those >75, monotherapy may be a more beneficial strategy due to the increased risk of NHL and NHL-related mortality with combination therapy. Due to the risk of HSTCL, combination therapy in young males may result in more deaths without providing substantially greater QALYs.

Mo1042 Evaluation of Treatment-Associated Harm for Irritable Bowel Syndrome With Constipation

A significant proportion of patients with irritable bowel syndrome (IBS) suffer from the constipation-predominant form (C-IBS). A number of therapeutic candidates have been evaluated for effectiveness in relieving the primary complaint of constipation. Since IBS is common, harm is an important consideration when selecting therapy.We present a systematic review and meta-analysis of adverse events and related dropouts in controlled trials for CIBS. Methods:We conducted a literature search to identify placebo-controlled trials evaluating treatments for C-IBS which have received a grade 1 rating (strong recommendation) from the ACG Task Force for IBS as well as emerging therapies which have successfully completed registered phase 3 trials. We included studies of least one week overall duration and only studies which reported adverse events (AE) as well as the number of dropouts due to AE. Our primary outcome of interest in assessing harm was relative dropouts due to adverse events. We also attempted to determine number needed to treat (NNT) and to harm (NNH) where appropriate by meta-analysis. A side effect profile of each drug was compiled based on the available data. Results: Eight clinical trials passed our exclusion criteria, four studies for selective serotonin reuptake inhibitors (SSRIs), three for lubiprostone and two for linaclotide. Based on the results of a combined FDA-registered phase III study, lubiprostone was not harmful relative to placebo and therefore a number-needed-to-harm could not be calculated while the NNT was 12.8. In one phase 3 study, the NNT of linaclotide was 5.1 though the NNH was 13. In this case, the number of subjects that would benefit from linaclotide before 1 harm event would be 2.6. In contrast, existing data from small, independent trials suggested that SSRIs are less harmful than placebo and therefore the data were not interpretable. The NNT for SSRIs was 2.9 though there was significant heterogeneity among studies (I2 = 59%) as well as poor quality and small overall sample size. Although side effects with lubiprostone included nausea and diarrhea, these were not statistically greater than placebo. For linaclotide, relative to placebo, diarrhea was greater with linaclotide (P<0.05). Conclusion: Lubiprostone appears to be safe in treating C-IBS with minimal harm leading to withdrawal. While nausea was a reported side effect, it did not lead to excessive withdrawal from study. In contrast, one patient withdrew from study due to side effects for every 2.6 with successful treatment on linaclotide suggesting significant harm. The safety of SSRIs in treating C-IBS is not clear unless large-scale trials are carried out that are sensitive to the occurrence and severity of known side effects in these drugs.