Digestive Disease Week 2013

Linaclotide Improves Abdominal and Bowel Symptoms

An analysis of two phase 3 trials found that a higher percentage of patients who received linaclotide to treat abdominal and bowel symptoms had clinically meaningful improvement compared with a group receiving placebo. The clinically meaningful thresholds were based on a patient’s assessment of adequate relief. Results were presented during a poster session at Digestive Disease Week 2013.

The US Food and Drug Administration (FDA) approved linaclotide in August 2012 to treat chronic idiopathic constipation and irritable bowel syndrome (IBS) with constipation. Linaclotide is an oral medication and a minimally absorbed guanylate cyclase-C agonist. The authors noted that an optimal patient-reported outcome had not been established, although adequate relief has been found to have “excellent qualitative and quantitative properties” as an outcome measure. However, they added that no one has compared adequate relief with the FDA-recommended responder end point.

In the two phase 3 trials, patients with IBS with constipation were randomly assigned to receive linaclotide or placebo once daily. Each day during the studies, patients reported abdominal symptoms (pain, discomfort, bloating, fullness, and cramping) as well as bowel symptoms (spontaneous bowel movement [SBM], complete SBM, stool consistency, and straining). The authors defined a spontaneous bowel movement as a bowel movement occurring without the use of a laxative, enema, or suppository on the day of or before the bowel movement. They defined a complete spontaneous bowel movement as having an SBM plus a feeling of complete evacuation. On a weekly basis, patients were also asked if they had adequate relief of their IBS symptoms within the past 7 days.

The weekly responder criteria as defined by the FDA were at least a 30% reduction in the worst abdominal pain and an increase in complete SBMs, both occurring in the same week. The authors used receiver operating characteristic methods to determine the thresholds of clinically meaningful abdominal and bowel symptom relief.

Of the 1602 patients in this analysis, 797 received a placebo pill and 805 were treated with linaclotide. During the 2-week baseline period, the mean SBM rate was 1.8 per week and the mean complete SBM rate was 0.2 per week.

Compared with the placebo group, patients who took linaclotide had significantly higher rates of clinically meaningful improvement for each of the abdominal and bowel symptoms (P≤.0001 for all comparisons). In addition, the patients in the linaclotide group had significant improvements in the following categories compared with the placebo group (P≤.0001 for all comparisons): average percent of weeks that patients had adequate relief, average percent of weeks that patients were weekly responders as defined by the FDA, and the average percent of weeks that patients met adequate relief and the FDA’s weekly responder criteria.

The authors noted that the FDA’s weekly responder criteria were more stringent than the adequate relief criteria. Most patients who were weekly responders per the FDA also had adequate relief, but 24% of patients in the linaclotide group and 18% of patients in the placebo group had adequate relief, but did not meet the FDA’s weekly responder criteria.—Tim Casey

This study was sponsored by Forest Laboratories, Inc. and Ironwood Pharmaceuticals, Inc.
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Treatment Options for Ulcerative Colitis

Clinicians have numerous options to treat patients with ulcerative colitis, a form of inflammatory bowel disease. The therapies include 5-amino-salacylic acid, thiopurine, and anti-tumor necrosis factor (TNF) agents such as infliximab. Surgical options include conventional ileostomy, continent ileostomy, ileal pouch-anal anastomosis, and ileorectal anastomosis.

Regardless of the treatment choice, the goal should be sustained disease control, which should be “the bar we all need to set,” said Marla C. Dubinsky, MD, Cedars-Sinai Medical Center, Los Angeles, CA, during a satellite symposium at Digestive Disease Week 2013. When dealing with ulcerative colitis, she suggested physicians aim for a normal endoscopy and mucosal healing and monitor the disease. They also need to focus on avoiding surgery. Dubinsky added that the combination of an immunomodulator and biologic drug has shown superiority to monotherapy.

There are numerous predictors of poor response or colectomy in ulcerative colitis patients, according to Dubinsky, including bandemia, prolonged flare, active infection, severe endoscopic lesions, and low hemoglobin. She added that the traditional methods to treat irritable bowel disease are symptom-based and sequential and based on acute severity rather than longitudinal changes. Remission is typically defined by the number of bowel movements, blood, or urgency, while flares are defined by patients as a change in their symptoms.

Dubinsky cited an Internet-based survey of 451 patients with ulcerative colitis in which 74% said having daily disease symptoms was normal. In addition, only 42% of respondents knew that remission meant patients had no symptoms.

Brian G. Feagan, MD, Robarts Clinical Trials, University of Western Ontario, Canada, followed Dubinsky with a discussion of the treatment options. He mentioned the conventional approach is sequential and is based on disease severity.

Feagan cited a study that found 17.9% of patients who took 9 mg of budesonide extended-release tablets had clinical remission at week 8 compared with 7.6% in a placebo group (P=.01). In the same trial, 13.2% of patients who took 6 mg budesonide extended-release tablets had clinical remission at week 8, a statistically significant increase compared with the placebo group (P=.01).

Corticosteroids are effective for induction of remission in ulcerative colitis, according to Feagan, but the effect is not durable and patients can become dependent on the drugs. He said prolonged exposure to corticosteroids is not recommended because they are associated with adverse effects. The most effective available therapy is the combination of a TNF antagonist plus azathioprine, according to Feagan.

Feagan also discussed tofacitinib, an oral janus kinase inhibitor. The US Food and Drug Administration (FDA) approved tofacitinib in November 2012 as a treatment for moderately to severely active rheumatoid arthritis. It is not approved for ulcerative colitis, but a phase 2 trial found the drug was superior to placebo when assessing the clinical response rate at week 8. Studies have shown no geriatric-specific problems upon using this agent, but serious infections are more common.  

Another option is adalimumab, which the FDA approved in September 2012 for moderate to severe ulcerative colitis. Feagan cited a study that found significantly more patients who took adalimumab had clinical remission at weeks 8 and 52 compared with patients who received placebo; however, there is a need for caution when using adalimumab in elders (≥65 years), as this population has had a higher incidence of infections and malignancies.—Tim Casey

The session was sponsored by Takeda Pharmaceutical Company Limited.
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Colorectal Cancer Screening and Colonoscopies

As screening rates for colorectal cancer have increased in recent years, the incidence and death rates due to the disease have declined. Still, approximately 22 million people in the United States have never been screened, and the survival rate for late-stage colorectal cancer remains small. During a satellite symposium at Digestive Disease Week 2013, physicians discussed the importance of colonoscopies and screening.

Carol A. Burke, MD, director, Center for Colon Polyp and Cancer Prevention, Cleveland Clinic, said that between 2003 and 2007, screenings prevented half of the anticipated new cases and deaths related to colorectal cancer. She added that an additional 1000 deaths could be avoided if the targets set by the US Department of Health and Human Services are met. As of now, half of colorectal cancer diagnoses are at a late stage when prognosis is poor, according to Burke, who mentioned that there is a 96% cure rate if colorectal cancer is diagnosed at an early stage.

There are different methods of colorectal cancer screening, including those recommended by the United States Multi-Society Task Force, the United States Preventive Services Task Force on Colorectal Cancer, and the American College of Gastroenterology (ACG). In each instance, patients are advised to undergo screening beginning at 45 or 50 years of age, have a fecal occult blood test every year, have flexible sigmoidoscopy every 5 years, and undergo a colonoscopy every 10 years.

The benefits of screening were observed in the National Polyp Study (N Engl J Med. 2012;366[8]:687-696), a trial that included patients prospectively referred for an initial colonoscopy between 1980 and 1990 and who had polyps, either adenomas or non-adenomas. After a follow-up period of up to 23 years, the authors found that colonoscopies were associated with several benefits, including reduced colorectal cancer incidence, reduced overall death rate, and reduced colorectal cancer death rate.

According to Burke, the ACG guidelines for high-quality colonoscopies include split-dose bowel preparation, documented cecal intubation, an average withdrawal time of at least 6 minutes, the use of effective techniques for polyp removal, and a close follow-up period following the piecemeal resection of large sessile lesions. She said that adenoma detection rates are an important quality indicator as well. The targeted adenoma detection rates are at least 25% in men and at least 15% in women.

Although adenoma detection rates are crucial, Burke said more than 70% of interval colorectal cancer cases are attributed to missed lesions. During the screening colonoscopy, there are numerous reasons for missing lesions and interval cancers, including incomplete bowel preparation, incomplete colonoscopy, short withdrawal time, incomplete adenoma resection, and rapid tumor progression.

Burke noted that adenoma detection rates are not the same as the serrated polyp detection rate. She defined sessile serrated adenomas as clinically significant lesions. There are 3 subtypes of serrated polyps: (1) hyperplastic polyps, (2) sessile serrated adenomas/polyps, and (3) traditional serrated adenomas. Hyperplastic polyps are very common, are located in the left colon, and are not precancerous. Sessile serrated adenomas/polyps and traditional serrated adenomas are precancerous, though, and are less common than hyperplastic polyps.

A cited study found that there was a modest accuracy of polyp histology and surveillance interval prediction. Before a 1-hour training session, 577 people correctly predicted surveillance intervals. After the training, 654 people had the right predictions. Another study revealed that endoscopists who were proficient in detecting nonpolypoid colorectal neoplasms had significantly higher adenoma detection rates for polypoid and flat adenomas.

Burke concluded that colonoscopy is a highly operator-dependent procedure and added that the causes of variable detection and how to correct low-level detection remain unclear.

Gastrointestinal Quality Measures
Glenn M. Eisen, MD, a gastroenterologist with The Oregon Clinic, Portland, OR, discussed the importance of collecting data to improve the quality of care. He cited the American Gastroenterological Association (AGA) Digestive Health Outcomes Registry, which captures patient data, identifies areas for improvement, and minimizes participation overhead and data-entry time. Its quality measures include documented colorectal cancer screening risk assessment before screening, colonoscopy within an appropriate follow-up interval, adverse events within 2 days of the procedure, colonoscopy completion rate, and adenoma detection rate.

The AGA and the American Society of Anesthesiology (ASA) have collaborated to form the GI Quality Improvement Consortium, Ltd., a nonprofit organization that has benchmarking reports and 84 data points and 11 measures. The measures include medical history and physical documentation; informed consent documentation; adequacy of bowel preparation; written discharge instructions for outpatients; ASA risk stratification; documentation of indication; cecal intubation with photo documentation; adenoma detection rates and immediate adverse events; and withdrawal time.

Eisen said healthcare professionals are currently using the Gastrointestinal Improvement Consortium, Ltd., to monitor training of fellows, for clinical research, as a resource quality measure, and to develop policies for the Centers for Medicare & Medicaid Services and private sector health insurers.

Whereas physicians are typically paid based on the volume of care, Eisen noted in the future they will be compensated based on the quality of care they deliver as well as their efficiency and patient satisfaction. He said there are already a few programs in place focused on quality. For example, physicians participating in a Blue Cross Blue Shield plan in North Carolina are required to submit data from a gastrointestinal specialty registry to be in the network for a client who covers 120,000 lives.

Although the Patient Protection and Affordable Care Act contains several provisions related to quality, the definition of quality healthcare is vague and debated by various parties, according to Eisen. He recommended that physicians, not payers, define quality because they will be dealing with the measures for years to come.—Tim Casey

The session was sponsored by Ferring Pharmaceuticals.
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Extended Duration Thromboprophylaxis for Venous Thromboembolism

Patients with venous thromboembolism (VTE) who took extended duration thromboprophylaxis had an incremental cost-effectiveness ratio of $8123 per quality-adjusted life year (QALY), according to a cost-effectiveness decision tree model. The threshold for the relative cost-effectiveness was a VTE incidence exceeding 2.53%. James C. Iannuzzi, MD, the study’s lead author, presented the results during a plenary session at Digestive Disease Week 2013.

“I think there is clear evidence as a payer that they should cover extended-duration thromboprophylaxis, especially if you only consider the cost threshold,” he said.

After Acting Surgeon General Steven K. Galson released a call to action to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) in September 2008, there were numerous inpatient prophylaxis initiatives, Iannuzzi said. However, the period of risk of developing DVT or PE extends beyond the inpatient setting. VTE consists of DVT and PE, he added.

Previous randomized control trials have demonstrated the efficacy of extended duration thromboprophylaxis, which Iannuzzi defined as 28 days of low molecular weight heparin (LMWH) following surgery. However, he said that most patients do not adhere to guidelines from the National Comprehensive Cancer Network (NCCN) and the American College of Chest Physicians (ACCP). The NCCN suggests using the same approach for all abdominal and pelvic oncologic resections, but the ACCP recommends a more selective approach for high- risk patients and considering patient preferences on costs. LMWH costs up to $1200 for a 28-day treatment course, according to Iannuzzi.

“It really becomes a balance between preventing VTE and the trade-offs of cost and also the discomforts [for] patients, particularly self-injections,” Iannuzzi said.

To develop their model, the authors conducted a literature review and made estimates on costs and utilization. They assessed costs in terms of 2013 US dollars, used QALY as the measure of effectiveness, and evaluated cost effectiveness using the incremental cost effectiveness ratio, which Iannuzzi defined as the difference in cost divided by the difference in effectiveness. They set the willingness to pay threshold at $50,000 per QALY.

In the model, patients undergoing oncologic abdominal surgery could receive 7 days of inpatient prophylaxis or 28 additional days of LMWH. At baseline, the authors made assumptions on utilization and the probability of VTE, medication compliance, death, and other factors. They used a database to estimate the costs of PE ($23,248.23), DVT ($21,539.76), post thrombotic syndrome ($14,362.71), generic LMWH ($705.74), branded LMWH ($871.74), and annual medical costs ($680).

For branded LMWH, the threshold at which extended duration thromboprophylaxis became the most cost minimizing was at 1.2% risk of developing postdischarge VTE. For generic LMWH, the threshold at which extended-duration thromboprophylaxis became the most cost minimizing was at 0.2% risk of developing postdischarge VTE. The cost-effectiveness threshold was found at 1.65% risk of developing postdischarge VTE for branded LMWH and at 0.88% risk of developing postdischarge VTE for generic LMWH.

“The cost of the drug made a large difference,” Iannuzzi said, and noted that more studies should be undertaken to evaluate quality of life after abdominal surgery. He also suggested providers implement risk scores to determine patients’ risks for VTE after being discharged.

The study had some “major” limitations, according to Iannuzzi, particularly because it was a simplified model. He noted that there was also a lack of utility weights for abdominal surgery.—Tim Casey