Eric D. Shah

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.

Estimating the Contribution of Acute Gastroenteritis to the Overall Prevalence of Irritable Bowel Syndrome

Background/Aims Recent studies reveal that acute gastroenteritis can precipitate irritable bowel syndrome (IBS) symptoms leading to the concept of post-infectious IBS. However, the overall contribution of gastroenteritis to the total IBS prevalence is unknown. In this exercise we try to estimate the contribution of gastroenteritis in IBS using the published literature and a longitudinal approach. Methods Existing literature was reviewed to determine the incidence of IBS after gastroenteritis, the rate of remission over time, data on rates of gastroenteritis in a given population and any patterns of resistance to these effects in human populations. This produced 3 models. The first assumed all humans were susceptible to gastroenteritis and its ability to produce IBS. The second assumed (using meta-analysis data) that 90% of humans in a given outbreak would be resistant to this effect. The third model used a high gastroenteritis exposure rate as might be seen in military deployment. Results In model 1, the prevalence was unrealistically high with an eventual steady state of 43.6% of the population affected by IBS. In a very conservative approach (model 2), steady state was achieved after 10 years to an overall prevalence of 8.9%. Interestingly, based on a high 1 year exposure rate such as military deployment, the maximum prevalence (steady state) was reached before 1 year suggesting high risk. Conclusions Although hypothetical in approach, based on conservative estimates in existing literature the contribution of gastroenteritis to the overall prevalence of IBS is substantial.

Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis

Objectives:Linaclotide and plecanatide are guanylate cyclase-C (GCC) agonists for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Our objective is to evaluate the efficacy and tolerability of GCC agonists based on data from multiple randomized controlled trials (RCTs).Methods:We searched PubMED, EMBASE, Cochrane databases, clinicaltrials.gov, major conference abstracts, Food and Drug Administration (FDA) websites, and United States Securities and Exchange Commission filings of drug sponsors to identify RCTs of CIC or IBS-C patients. We assessed efficacy based on FDA-approved composite responder endpoints, diarrhea as an adverse event, and study withdrawal owing to diarrhea for each therapy. Trial results were pooled using DerSimonian and Laird random effects model of meta-analysis and exact logistic regression when appropriate with 95% confidence intervals. Meta-regression was performed to compare outcomes between therapies adjusting for placebo event rate.Results:Eight linaclotide trials (five CIC; three IBS-C) and seven plecanatide trials (four CIC; three IBS-C) evaluating 10,369 patients met inclusion criteria. FDA publications documented that different definitions for diarrhea were used in linaclotide vs. plecanatide trials. Both drugs were efficacious in treating CIC (linaclotide 72 μg (Odds ratio (OR)=3.11, 95% CI 1.81–5.34); linaclotide 145 μg (OR=3.25, 2.15–4.91); plecanatide 3 mg (OR=1.99, 1.57–2.51)) and IBS-C (linaclotide 290 μg (OR=2.43, 1.48–3.98); plecanatide 3 mg (OR=1.87, 1.47–2.38); plecanatide 6 mg (OR=1.92, 1.48–2.48)). Diarrhea occurred in excess of placebo in treating CIC (linaclotide 72 μg (OR=3.07, 1.97–4.77); linaclotide 145 μg (OR=3.70, 2.69–5.10); plecanatide 3 mg (OR=3.86, 1.83–8.12)) and IBS-C (linaclotide 290 μg (OR=8.02, 5.20–12.37); plecanatide 3 mg (OR=5.55, 1.62–19.00); plecanatide 6 mg (OR=4.13, 1.57–10.83)). Based on meta-regression, there were no statistically significant differences between therapies in odds ratios for efficacy, diarrhea, or diarrhea-related study withdrawals.Conclusions:Both linaclotide and plecanatide demonstrate similar efficacy and tolerability in treating IBS-C and CIC. No differences in odds of diarrhea were seen between linaclotide and plecanatide.

Lower and Upper Gastrointestinal Symptoms Differ Between Individuals With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation

Background/Aims We evaluated the distribution of lower and upper gastrointestinal (GI) symptoms among individuals with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in a nationwide survey. Methods Individuals (≥ 18 years of age) were identified from a nationwide sample of > 70 000 United States adults. Participants completed the National Institutes of Health GI Patient Reported Outcomes Measurement Information System (NIH GI-PROMIS) questionnaire. Symptom frequency and intensity in the prior 7 days were assessed using validated PROMIS scores. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to compare symptom prevalence in IBS-C vs CIC, and one-way ANOVA was used to assess differences in PROMIS scores. Regression analysis was performed to adjust for demographic variables. Results Nine hundred and seventy adults met eligibility criteria (275 with IBS-C, 734 with CIC). Demographics were similar among groups except for education, marital and employment status, and income. Adjusting for demographic differences, GI-PROMIS scores of global GI symptoms were higher in IBS-C (251.1; 95% CI, 230.0–273.1) compared to CIC (177.8; 95% CI 167.2–188.4) (P < 0.001). Abdominal pain was more prevalent (OR, 4.3; 95% CI, 2.9–6.6) and more severe (P = 0.007) in IBS-C. Constipation was more severe in IBS-C (P = 0.011). Incontinence was more common (OR, 2.9; 95% CI, 1.3–6.3) but just as severe (P = 0.389) in IBS-C versus CIC. Regarding upper GI symptoms, the prevalence of dysphagia, heartburn, and nausea were similar. However, IBS-C individuals had more severe heartburn (P = 0.001). Conclusion GI symptoms are generally more severe in IBS-C compared to CIC, however abdominal pain, bloating, and upper GI symptoms still commonly occur in CIC.

Sa1158 The Number of Drug Side Effects Is Associated With Greater Efficacy in IBS Clinical Trials: The Potential Influence of Unblinding

and after cholecystectomy were used as surrogate measure for resource utilization. RESULTS: Within the time frame of the study, 419 patients (79.4% women; age 42.4±0.7 years) were diagnosed with biliary dyskinesia, with all but 24 (94.3%) undergoing cholecystectomy. The mean duration of symptoms was 19.8±7.5 months; in 129 (30.8%) patients, symptoms had started less than 3 months prior to evaluation. Functional gallbladder imaging revealed a mean gallbladder ejection fraction of 22.4±1.0%, with 66 (15.8%) patients having normal results. Patients completed 3.2±0.1 diagnostic tests prior to being scheduled for cholecystectomy. Appropriate follow up data were available for 209 patients. Within the 12 months interval, ER visit and hospitalizations decreased from 1.0±0.1 to 0.7±0.2 (P=0.07) and from 0.3±0.04 to 0.26±0.06 (P=0.69), respectively. In univariate analyses, age, shorter disease duration, normal gallbladder ejection fraction, a history of chronic back pain and use of prescription opioids were associated with ongoing resource utilization after surgery. Using a multiple nonlinear regression model, younger age (OR 3.2; 95% CI: 1.2-8.2) and use of opioid analgesics (OR 3.7; 95% CI: 1.3-10.2) were independent predictors of ongoing resource utilization. CONCLUSIONS: Our data demonstrate a lowered threshold for cholecystectomy, as more than one third of the patients did not meet current consensus criteria for biliary dyskinesia. While we did not address the impact of surgery on symptoms, surgery has a marginal effect on resource utilization. The impact of coexisting disorders and opioid use on ongoing healthcare needs points at the role of non-gastrointestinal factors and argues against surgical approaches.

How to Become a Physician Executive: From Fellowship to Leadership

Finding a Mentor Gastroenterologists interested in executive leadership often struggle to find a mentor who is a successful physician executive and who has the time and ability to help you understand your own leadership skills, who can define specific knowledge needed, and who actively participates in health system administration. Often these physicians have a defined leadership role within the division, department, professional faculty plan, or hospital (and may not be a gastroenterologist).

Sa1339 A Comparison of Psychological Associations With IBS and Ulcerative Colitis

G A A b st ra ct s severity of gastrointestinal symptoms in FD and GvHD to identify potential differences in symptom severity and manifestation. Methods: Sixty-seven patients with aGvHD (I°-III°) and 45 patients with FD according to ROME III criteria were recruited. The following key symptoms were assessed utilizing the standardized Gastrointestinal Symptom Score: epigastric pain, cramps, fullness, early satiety, nausea and vomiting. AX and DEP were measured with the Hospital Anxiety and Depression Scale. Patients scoring 0-7 on each subscale were considered not having a psychological co-morbidity. Patients with 8-10 were categorized as probable (p) AX/DEP while patients scoring ≥11 were considered having a relevant (r) AX/ DEP. Analysis was performed by Spearman rank correlations and T test. Results: In GvHD pAX was found in 12/67, rAX in 6/67, pDEP in 4/67 and rDEP in 8/67. In FD pAX was observed in 12/45, rAX in 8/45, pDEP in 11/45 and rDEP in 6/45. Overall AX (p=0.54) and DEP (p=0.75) scores did not differ between FD and GvHD. AX in GvHD was correlated with severity of pain (r=.25, p=0.04), fullness (r=.43, p,0.001), satiety (r=.40, p=0.001), nausea (r=.36, p=0.003) and vomiting (r= .40, p=0.001). In FD AX correlated with pain (r=.44, p,0.028), fullness (r=.38, p,0.001), satiety (r=.23, p=0.03), vomiting (r=.32, p= 0.002). FD patients without AX showed significantly more severe cramps and nausea but less vomiting compared to GvHD without Ax. In FD patients with pAX and rAX pain was more prominent while vomiting was less evident compared to GvHD with pAX and rAX. DEP was associated with pain (r=.58, p,=0.001), cramps (r= .53, p,0.001), fullness (r= .64, p,0.001), satiety (r=.50, p,0.001), nausea (r=.43, p,0.001) and vomiting (r= .48, p,0.001) in GvHD but only with pain (r=.23, p ,0.001) in FD. FD patients with and without DEP were characterized by increased pain but decreased early satiety and less vomiting compared to respective GvHD groups. Conclusion: Psychological co-morbidity is closely linked to symptom severity in FD and organic GI disease. While patients with FD experience more pain, vomiting is more severe in GvHD. These differences may indicate different underlying pathophysiological mechanisms rather than psychologically driven factors.

1039 Functional Net Value (FNV): an Important Consideration in Clinical Evaluation of IBS Pharmacotherapy

Background: Radiation proctitis (RAP) is defined as damage to the rectal mucosa resulting from radiotherapy to adjacent pelvic organs. More than 50 % of patients undergoing radiotherapy for prostate cancer (PC) will encounter symptoms such as diarrhea, blood and mucus in stool and tenesms that might alter qualitiy of life and might be dose limiting. The symptoms of radiation proctitis can be quantified by the acute EORTC/RTOG lower GI toxicity or the RAP score . Material and Methods: Patients undergoing radiotherapy (XRT) for PC were randomised to rectal budesonide (BUD) or placebo (PLB) treatment over 8 weeks. EORTC/RTOG lower GI toxicity score, RAP score and quality of life scores were taken at baseline and after 2, 4, 8 and 14 weeks as well as after 1 year. Flexible rectoscopy and assessment of the Vienna rectoscopy score (VRS) was done at baseline, after 8 weeks, 14 weeks and 1 year. 17 patients were included (n=8 budesonide, n=9 placebo) into the study. Results: 6/8 BUD patients and 6/9 PLB patients developed clinical signs of acute radiation proctitis, i.e. acute EORT/RTOG lower GI toxicity ≥ 1 for at least 2 consecutive days, during 8 weeks of treatment (p=0.8167). However, BUD ameliorated the severity of RAP by significantly reducing stool frequency at week 14 and after 1 year and numerically the number of tenesms at week 8. The endoscopic score for late radiation proctitis was diminished in the budesonide group compared to placebo. Conclusions: Rectal treatment with budesonide did not significantly prevent acute radiation proctitis in this pilot study. However, clinical symptoms of proctitis could be significantly reduced and the appearance of late radiation proctitis was diminished. Therefore BUD deserves further evaluation in the context of high dose XRT with curative intent to prevent or to ameliorate side effects that might be dose limiting.

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.