Reports

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Digestive Disease Week 2006

Los Angeles, California / May 20-25, 2006

The management for ulcerative colitis (UC) has been sometimes characterized as an effort to slow the progression to serious complications. Although natural history studies suggest the proportion of patients who require treatments reserved for moderate to severe disease, such as infliximab, cyclosporine and surgery, increases over time, a large proportion of patients who present with mild to moderate disease never progress to major complications or to therapies reserved for severe disease. Compliance with 5-aminosalicylate (5-ASA), the therapy most commonly prescribed in mild to moderate disease, may be a key factor in sustained control.

Disease Mostly Quiescent at One Year

“The risk of uncontrolled disease in patients on therapy one year after diagnosis is lower than most people think it is,” stated Dr. Gary R. Lichtenstein, Director, Inflammatory Bowel Disease Program, University of Pennsylvania, Philadelphia. While he acknowledged that 20% of patients demonstrate moderate to severe disease activity at one year, many of them present with severe disease or respond poorly to initial therapy. In patients with mild to moderate disease at presentation, there are substantial data to support non-adherence as a risk factor for relapse. Among these are the higher rates of relapse outside of clinical trials, where closer patient surveillance and encouragement are likely to increase the proportion of patients who take their medication at prescribed doses on schedule.

Due to concern over non-compliance, particularly among patients whose motivation may diminish after symptoms are controlled, simpler dosing schedules, behaviour modification, and education may be as important as the therapies themselves. While non-adherence to therapy is hardly unique to UC, its consequences are particularly severe. In one study, the remission rate among those compliant with mesalamine (5-ASA) remained above 90% at 24 months vs. approximately 40% in those who were not (P<0.001).

“Pharmacologic and non-pharmacologic interventions by physicians can improve medication compliance, and this has very important implications for outcome in inflammatory bowel diseases,” maintained Dr. Sunanda V. Kane, Section of Gastroenterology, Associate Professor of Medicine, University of Chicago, Illinois. “This is something to which we need to be more sensitive in order to improve outcomes.”

Simplifying Dosing

Of the pharmacologic strategies, the most significant may be the development of extended-release, once-daily therapies that reduce the burden of compliance. In a study comparing q.d. to conventionally-dosed mesalamine published by Dr. Kane in 2003, the compliance was 100% with the q.d. regimen at three months vs. 70% for the conventional regimen (P=0.04). Although the advantage of the q.d. regimen diminished over time, adverse events, another important factor in compliance, may have played a role.

More recently, an experimental q.d. extended-release formulation of mesalamine that avoids the peaks and troughs in drug concentration that can exacerbate adverse events has shown promise for simplifying therapy and minimizing adverse events. In a phase III study evaluating two doses of this agent, known as SPD476, adverse events in the higher dose were similar to those in the lower dose.

According to Dr. Lichtenstein, “Two phase III multicentre, randomized, double-blind, controlled studies were conducted with 423 patients with moderately active UC that could be evaluated. Treatment with the 4.8 g/day dose provided a statistically significant efficacy benefit over the 2.4 g/day dose, but both doses had similar safety profiles and both were well tolerated.”

In one of the trials, the two doses of SPD476—which employs a multi-matrix system in the tablet to extend the period of release of active therapy and improve delivery through the colon—were compared to placebo. The other trial was also placebo-controlled but included a conventional mesalamine formulation that was dosed at a total of 2.4 g/day in a three-times-daily schedule. Treatment success was achieved in 72% of patients at the higher dose of SPD476 vs. 58% of those at the lower dose. In the study that included an arm with mesalamine in a conventional schedule, the remission rates, which was the primary end point, were 40.5% and 41.2% for SPD476 in the lower and higher doses, respectively, vs. 32.6% for the t.i.d. mesalamine and 22.1% for placebo. Although the advantage of SPD476 over t.i.d. mesalamine did not reach statistical significance, the t.i.d. mesalamine, unlike SPD476, was not significantly better than placebo.

Disease Quiescence May Promote Non-Adherence

The need for simplified dosing of 5-ASA medications in mild to moderate UC is supported by patient survey data that suggest efficacy is a double-edge sword. While control of symptoms is clearly the priority in seeking therapy, patient compliance tends to diminish as symptoms are controlled, creating the risk of relapse. According to respondents of a survey of the members of the Crohn’s and Colitis Foundation of America—an organization that might reasonably be expected to attract individuals most interested in learning about how to control their disease—only about one-third of patients reported that they never failed to take their medication. Most of the remaining respondents asserted that they forgot their medication only once a week or less, but about 10% acknowledged that they failed to take medication more frequently.

However, self-reported adherence rates do not appear to be credible, according to Dr. Kane, who has published on this subject. She cited a trial in which 98 patients prescribed mesalamine were interviewed for compliance and other characteristics, such as disease activity index. Spot samples of urine were assayed for 5-ASA levels. When self-reports were evaluated in the context of the urine analyses, no relationship could be observed. The results included patients taking more medication than they reported as well as patients taking less.

“There was no correlation at all between what the patient reported about their compliance and the amount of drug they were actually taking. The exception was patients who said that they never took their drugs. These patients were the only ones whose self-reports were accurate,” Dr. Kane told delegates.

Recurrence Increases Fivefold in Non-adherent Patients

Research at Dr. Kane’s institution has demonstrated a high rate of recurrence in non-adherent patients. In a multivariate analysis, the hazard ratio (HR) for recurrence from non-adherent patients was increased by more than fivefold (5.47, 95% CI; 2.26-13.22; P=0.001). Other risk factors for recurrence identified in this study were less than 12 months of initial disease remission on treatment (HR 2.65) and positive family history (HR 2.42). In a separate study, Dr. Kane found that non-adherence in patients with quiescent UC is due to forgetfulness (60%) rather than lack of perceived benefit (20.4%), fear of adverse events (3.4%) or cost issues (3.4%). She suggested that physician counselling about the importance of adherence, even during periods of quiescent disease, could make a difference, citing a small study she conducted with 21 patients taking only about half of their prescribed therapy.

“Six months after a physician interview [outlining the critical importance of adherence], 10 patients improved their adherence and were taking more than 80% of their prescribed therapy. Over this follow-up, only one of the 10 newly adherent patients experienced a clinical relapse vs. four of the 11 who continued to be non-adherent,” Dr. Kane reported. Quoting former US surgeon general Dr. Everett Koop, Dr. Kane said, “Drugs don’t work in patients who don’t take them.”

Not all patients with mild to moderate disease are well controlled on an oral regimen of 5-ASA, but the data suggest that more patients could remain in remission even on a once-daily regimen if educated and motivated to remain adherent, even in the absence of active disease. The goal of keeping patients in remission may not be confined to issues of symptom control and quality of life. Rather, Dr. Lichtenstein cited data suggesting that maintenance of mucosal healing might improve long-term outcome.

“There is a growing sense that less inflammation is better, and I think we are evolving to that as a clinical goal,” observed Dr. William J. Sandborn, Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota. He cautioned that clinical disease severity and endoscopic end points do not necessarily correlate, providing another impetus for patients to remain adherent to therapy even in the absence of clinical symptoms.

Summary

For many patients with mild to moderate UC, the key to longer remissions may not be more potent therapies but better compliance to existing therapies. The data supporting the major role played by non-adherence in relapse, particularly in patients with quiescent disease, has supported the development of simpler and better-tolerated therapies. When combined with patient education to increase motivation, q.d. regimens may play an important role in boosting adherence to improve outcome.