Sulfasalazine Revisited

A Meta-Analysis of 5-Aminosalicylic Acid in the Treatment of Ulcerative Colitis

1 April 1993 | Volume 118 Issue 7 | Pages 540-549

Purpose: To assess the effectiveness of the newer 5-aminosalicylic acid (5-ASA) delivery systems compared with placebo or sulfasalazine for the treatment of active ulcerative colitis and for the maintenance of remission.

Data Sources: Pertinent studies were selected using the MEDLINE and BIOS (1981 to 1992) data bases, reference lists from published articles, reviews, symposia proceedings, and abstracts from major gastrointestinal meetings.

Study Selection: Randomized controlled trials of 5-ASA compared with placebo or sulfasalazine of a minimum of 4 weeks duration for active disease and a minimum of 6 months for maintenance of disease remission. Sixteen trials of 5-ASA for active disease, published either in abstract or full manuscript, were available. Eleven trials of 5-ASA for maintenance of remission were also reviewed.

Data Extraction: Crude rates for either induction of remission (active disease studies) or maintenance of remission (relapse-prevention trials) based on the intention-to-treat principle were extracted from the studies by two independent observers. Each study was given a quality score, based on predetermined criteria.

Results: Studies were placed in three groups: 5-ASA compared with placebo, 5-ASA compared with sulfasalazine for active disease, and 5-ASA compared with sulfasalazine for maintenance of remission. 5-Aminosalicylic acid was superior to placebo in the treatment of active ulcerative colitis (pooled odds ratio, 2.02; 95% CI, 1.50 to 2.72). A dose-response effect for 5-ASA existed (P < 0.001). For active disease, the pooled odds ratio for 5-ASA compared with sulfasalazine was 1.15 (CI, 0.83 to 1.61). When 5-ASA was compared with sulfasalazine for maintenance of disease remission, the pooled odds ratio was 0.85 (CI, 0.64 to 1.15). Withdrawal rates and reported side effects were similar for 5-ASA compared with placebo- or sulfasalazine-treated patients.

Conclusions: Although the newer 5-ASA preparations in a dose of at least 2 g/d are more effective than placebo in the treatment of ulcerative colitis, insufficient evidence exists to suggest that they are superior to sulfasalazine. Although they offer a benefit to the sulfasalazine-sensitive patient, use of 5-ASA preparations instead of sulfasalazine in the treatment of ulcerative colitis cannot yet be substantiated.

The first major therapeutic advance in ulcerative colitis was the discovery of sulfasalazine (sulfapyridine bonded to 5-aminosalicylic acid [5-ASA]) [1], which was the first effective therapeutic agent for active ulcerative colitis [2] and for maintenance of remission [3]. Currently, all patients with ulcerative colitis in remission take sulfasalazine indefinitely [4]. The maximum dose of sulfasalazine is limited by the frequency of adverse drug reactions [5]. Approximately 30% of patients taking sulfasalazine report adverse reactions; many are idiosyncratic but others are dose related.

Azad Khan [6] and others [7] showed that 5-ASA was the active moiety of sulfasalazine and that sulfapyridine functioned only as a carrier. Many investigators believed that the development of a new delivery system would allow the use of higher doses of 5-ASA, which might provide additional therapeutic benefits to patients. Currently five new preparations are available. They can be broadly classified into three categories: pH-dependent formulations; microsphere formulations; and those formulations that bind 5-ASA to another carrier, which requires splitting of the diazo bond by bacteria. Although generic names are generally preferable, in this situation proprietary names are required to identify each medication by its release mechanisms.

The first 5-ASA delayed-release, pH-sensitive preparation (Asacol) (Proctor & Gamble Pharmaceuticals, Inc., Norwich, New York) is a pellet of 5-ASA coated with a resin (Eudragit S) that dissolves when the pH of the fecal contents is more than 7 [8]. A second pH-dependent, 5-ASA preparation (Claversal, Salofalk, Mesasal, Rowasa) is coated with another resin (Eudragit L) that dissolves at a fecal pH that is more than 6 [9]. The only currently available microsphere preparation of 5-ASA (Pentasa) consists of 5-ASA coated with an ethylcellulose that allows for slow release of the medication beginning in the duodenum and extending into the colon [9]. The alternative-carrier approach includes binding 5-ASA to another 5-ASA molecule, olsalazine (Dipentum, Kabi Pharmacia, Piscataway, New Jersey), or to various benzoic acid derivatives, such as balsalazide [10] or benzalazine [11].

The newer products are more expensive for patients, and their superiority over sulfasalazine has not yet been proven. To better define the role and efficacy of these new 5-ASA-containing medications, we did a meta-analysis of the randomized, controlled trials comparing them with either placebo or sulfasalazine.

Methods

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A literature search was done using the MEDLINE and BIOS data bases for January 1981 to May 1992 and using the MESH headings "ulcerative colitis" and "aminosalicylates." Citations were limited to those published in English. A manual search sought additional citations using references in articles retrieved from the computerized search as well as review articles, proceedings from symposia, and textbooks. Studies of oral 5-ASA preparations for the acute and maintenance treatment of ulcerative colitis were accepted for analysis if they were randomized, controlled, of parallel design, and had a treatment duration of a minimum of 4 weeks for acute therapy and of 6 months for maintenance therapy.

Studies accepted for analysis were reviewed independently by two of the authors (LRS and GRM), and the results of each study were recorded. For reports of acute therapy, the numbers of patients with clinical, endoscopic, or histologic remission as defined in each study were recorded. For studies of maintenance therapy, the number of patients remaining in remission clinically or endoscopically were recorded. Results were recorded on an intention-to-treat basis. No uniform definition of a response existed across the studies. Where possible the numbers of patients having adverse effects or withdrawing from therapy because of adverse events were recorded. Original investigators were contacted when necessary to clarify points regarding inclusion criteria or data. We did a blinded quality analysis of each study we selected, using the criteria and methods outlined by Chalmers and colleagues [12] (Appendix 1 Table 1, Table 2, Table 3). Any discrepancies between reviewers about the retrieved data or quality assessment were settled by consensus.

View this table: [in this window] [in a new window]   Appendix Table 1. Quality Assessment Scoring System: Study Protocol*

 

View this table: [in this window] [in a new window]   Appendix Table 2. Quality Assessment Scoring System: Statistical Analysis

 

View this table: [in this window] [in a new window]   Appendix Table 3. Quality Assessment Scoring System: Presentation of Results

 

Studies were separated into three groups: 5-ASA compared with placebo for acute therapy, 5-ASA compared with sulfasalazine for acute therapy, and 5-ASA compared with sulfasalazine for maintenance therapy. Each group was analyzed separately. For each group, homogeneity was tested using the method outlined by DerSimonian and Laird [13]. Pooled odds ratios with 95% confidence intervals (CIs) were calculated using a commercially available, computerized biostatistical program [14]. To confirm the degree of homogeneity, all of the individual trial 95% CIs were also graphed to confirm that a substantial overlap existed for all of the individual CIs (see Figures 1, 2, and 3). (Note that if the CIs for a pooled odds ratio include unity, the evidence supporting an actual difference is weak or inconclusive.) If possible, results were also subgrouped according to the dose of 5-ASA and the specific 5-ASA preparation used; these subgroups were analyzed in a similar manner. Adverse effects and withdrawals were analyzed by pooled odds ratio and by combining the adverse effects for each group; the overall results were analyzed using chi-square tests. The Fisher exact test was used when appropriate for small counts.

View larger version (18K): [in this window] [in a new window]   Figure 1.

 

View larger version (17K): [in this window] [in a new window]   Figure 2.

 

View larger version (19K): [in this window] [in a new window]   Figure 3.

 

Results

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From the more than 150 citations collected by the literature search, 59 trials of oral 5-ASA therapy for mild-to-moderate ulcerative colitis as defined by Truelove and Witts [15] were identified. Twenty-seven trials (45.7%) Table 1 and Table 2 met the inclusion criteria and were included in the analysis [11,16-41]. Thirty-two studies were excluded. Fifteen of these studies were "open label" and were excluded due to lack of randomization [8, 42-55]. Of the remaining 17 studies, the reasons for exclusion included design other than controlled, with parallel design in 3 studies [56-58]; duration less than 4 weeks in 2 studies [59, 60]; single-center reports of patients who were abstracted from larger multicenter trials in 2 [61, 62]; data presented in an inappropriate form for our analysis in 3 abstracts [63-65]; 5 abstracts subsequently published [66-70]; and 2 papers also being published in symposia [71, 72].

View this table: [in this window] [in a new window]   Table 1. Characteristics of Each Trial Included in the Meta-Analysis

 

View this table: [in this window] [in a new window]   Table 2. Treatment Regimens and Outcome for Each Trial Included in the Meta-Analysis

 

Quality scores, from Chalmers criteria [12], ranged from 0.25 to 0.80, with a median of 0.62 (see Table 1). Scores were normally distributed [Shapiro-Wilks test for normality = 0.920, P = 0.13]. Excellent correlation existed between observers, with a correlation coefficient of 0.88 (P < 0.001). Most studies lost points for omissions about study design and use of statistics. No apparent effect of study quality on the results existed within each group.

5-Aminosalicylic Acid Compared with Placebo for Acute Therapy

Eight trials, comprising 1007 patients, examined oral 5-ASA compared with placebo for acute mild-to-moderate ulcerative colitis [18, 23-25, 27, 33, 37, 39]. Studies were homogeneous (P > 0.2). The pooled odds ratio for complete remission combining all 5-ASA preparations with all doses was 2.02 (CI, 1.50 to 2.72) (Figure 1). Results were not significantly different if abstracts were excluded from the analysis. If the results were grouped according to the dose of 5-ASA used, a dose-dependent trend was apparent (Table 3). For patients who received less than 2 g of 5-ASA, the response was not different from placebo. The pooled odds ratio, for patients receiving at least 2 g/d of 5-ASA, showed improvement compared with placebo.

View this table: [in this window] [in a new window]   Table 3. Pooled Odds Ratios for Studies of 5-Aminosalicylic Acid Compared with Placebo by Dose

 

No significant differences in response could be shown between any of the 5-ASA preparations (Table 4). Only three studies [24, 27, 39], all with Dipentum, had sufficient data to determine an endoscopic response to therapy. The pooled odds ratio for endoscopic response was 4.97 (CI, 2.50 to 9.85).

View this table: [in this window] [in a new window]   Table 4. Pooled Odds Ratios for 5-Aminosalicylic Acid Therapy for Ulcerative Colitis by Preparation

 

5-Aminosalicylic Acid Compared with Sulfasalazine for Acute Therapy

Eight trials, involving 553 patients, compared 5-ASA with sulfasalazine for the acute treatment of ulcerative colitis [11, 16, 19, 29-31, 34, 35]. Studies were homogeneous (P > 0.2). The pooled odds ratio for complete remission, after combining all 5-ASA preparations and comparing them with sulfasalazine, was 1.15 (CI, 0.83 to 1.61) (Figure 2). The result was similar if patients entering into complete remission were combined with those showing improvement; pooled odds ratio was 1.20 (CI, 0.86 to 1.69). The results did not differ significantly when abstracts were excluded. If studies were subgrouped according to the dose of 5-ASA used, no evidence existed for a dose-response relationship. Trials using 2 g/d of 5-ASA had a pooled odds ratio of 1.24 (CI, 0.79 to 1.94), [11, 16, 29, 31, 34, 35], whereas those using less than 2 g/d had a pooled odds ratio of 1.12 (CI, 0.69 to 1.81) [19, 30, 34].

No significant differences in efficacy existed between the various 5-ASA preparations when compared with sulfasalazine (see Table 4). If endoscopic response was considered, the pooled odds ratio from seven studies was 1.25 [CI, 0.85 to 1.83] [11, 16, 29-31, 34, 35]. No difference in endoscopic response existed between 5-ASA preparations compared with sulfasalazine. Olsalazine (Dipentum) in three studies [16, 29, 31] had a pooled odds ratio for endoscopic response of 1.13 (CI, 0.59 to 2.20), and two trials using Asacol [34, 35] had a pooled odds ratio of 1.61 (CI, 0.78 to 3.32).

5-Aminosalicylic Acid for Maintenance Therapy

Eleven trials, involving 1153 patients, compared 5-ASA with sulfasalazine for maintenance therapy [17, 19-22, 26, 28, 32, 36, 38, 40]. Only one placebo-controlled trial of 5-ASA for maintenance therapy was done [41]. The analysis was, therefore, restricted to the former group of studies comparing 5-ASA with sulfasalazine. These trials were homogeneous (P > 0.2) (Figure 3). Ten trials (927 patients) defined clinical response as maintaining remission during a 12-month period. The pooled odds ratio for these studies was 0.85 (CI, 0.64 to 1.15) (Figure 3). Results did not differ significantly if abstracts were excluded from the analysis. When analyzed according to the dose of 5-ASA used, five trials had treatment arms using 1 g/d of 5-ASA [17, 20, 21, 26, 28]. The pooled odds ratio for these trials at higher doses (0.89; CI, 0.55 to 1.44) was not significantly different from the pooled odds ratio (0.82; CI, 0.56 to 1.19) in the five trials using less than 1 g/d of 5-ASA [19, 22, 32, 36, 38].

No significant differences existed between the various 5-ASA products (see Table 4). One recent study [using olsalazine] defined relapse using endoscopic criteria [40]; the odds ratio for this single study was 0.84 (CI, 0.50 to 1.41).

Adverse Effects and Withdrawals from Therapy

In most reports, it was difficult to determine the exact numbers of patients having adverse effects or withdrawing from therapy because of adverse events. Frequently studies only reported the percentages of patients with a specific symptom. In three trials examining 5-ASA compared with placebo [23, 25, 33], 31% of treated patients had adverse effects compared with 33% of placebo patients. The pooled odds ratio for developing side effects was 0.96 (CI, 0.58 to 1.58). In six trials it was possible to determine patients withdrawing from therapy [23-25, 27, 33, 37]. Overall, 6% of 5-ASA-treated patients compared with 4% of placebo patients were withdrawn from therapy. The pooled odds ratio for being withdrawn from therapy was 1.58 (CI, 0.72 to 3.49).

In five trials examining 5-ASA compared with sulfasalazine for acute therapy [11, 29-31, 35], 16% of 5-ASA-treated patients had adverse effects compared with 23% of sulfasalazine-treated patients; (P = 0.07). The pooled odds ratio for developing adverse effects in these studies was 0.68 (CI, 0.44 to 1.03). Four trials examined withdrawals from therapy [11, 29, 30, 34]. Overall, 4% of 5-ASA-treated patients withdrew compared with 7% of sulfasalazine-treated patients (P > 0.2). The pooled odds ratio for withdrawal was 0.60 (CI, 0.25 to 1.44).

In seven maintenance trials of 5-ASA compared with sulfasalazine, it was possible to examine side effects [17, 19, 22, 26, 28, 36, 37]. Overall 17% of 5-ASA-treated patients compared with 18% of sulfasalazine-treated patients had an adverse effect (P > 0.2). The pooled odds ratio for adverse effects was 1.17 (CI, 0.77 to 1.75). In six trials it was possible to analyze withdrawals from therapy [17, 21, 22, 26, 28, 36]; overall 8% of 5-ASA-treated and 9% of sulfasalazine-treated patients were withdrawn from therapy because of side effects. The pooled odds ratio for being withdrawn was 1.01 (CI, 0.59 to 1.74). In most of the studies, the common adverse side effects included diarrhea, nausea, dyspepsia, abdominal pain, and headache. Because side effects were inconsistently reported, we were unable to examine specific adverse side effects.

Discussion

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After more than 10 years of investigation of the newer 5-ASA compounds involving thousands of patients, clear conclusions about the various medications cannot be made. Initial studies hypothesized that the new 5-ASA formulations would require approximately 40% of the dose compared with the parent compound [8]. For example, in active ulcerative colitis approximately 1.6 g of 5-ASA (corresponding to 2.5 g of sulfasalazine) would suffice. The present analysis provided no evidence to support such a ratio, because 1.6 g of 5-ASA was not superior to placebo. In fact, our review suggests that at least 2 g of 5-ASA must be given in active disease. Evidence for a response to increasing doses of 5-ASA is limited, but a slight trend exists for a dose-response effect, although the CIs vary widely.

Is one 5-ASA preparation better than the others? In the acute studies, none of the newer 5-ASA preparations was superior to sulfasalazine. The newer 5-ASA preparations were essentially as efficacious as sulfasalazine; however, the CIs are so wide that definitive conclusions cannot be made. Although the accepted trials involved more than 2700 patients, our analysis has relatively low statistical power to detect actual differences, particularly when sulfasalazine and the newer 5-ASA delivery systems are compared. If the benefit from the newer 5-ASA preparations is modest, then trials involving hundreds of additional patients would be required. When the studies were grouped by specific 5-ASA preparations, the ability to detect significant differences compared with sulfasalazine was lost.

When the newer 5-ASA preparations are compared with sulfasalazine for active disease, evidence supports a slight enhancement of therapeutic efficacy, but it cannot be statistically corroborated. On a molar basis, the doses of 5-ASA used in recent trials correspond to the equivalent of up to 10 g of sulfasalazine per day. In most trials, however, only 2 to 4 g of sulfasalazine was given. For maintenance therapy, none of the newer 5-ASA agents was more efficacious than sulfasalazine. The lack of superiority for the newer 5-ASA preparations compared with sulfasalazine raises a variety of questions, including "What is the mechanism of action of 5-ASA?" Inhibition of leukotriene production [73] and scavenging of free radicals [74] have been theorized as possible mechanisms. Controversy continues as to whether sulfasalazine itself has other effects that are related to the parent compound and not to 5-ASA [75, 76]. Thus, sulfasalazine could offer therapeutic advantages in addition to those related to 5-ASA. Continuing to increase the oral dose of 5-ASA might not provide further therapeutic gain.

Sulfasalazine, which requires bacterial action, may be a more efficient carrier for 5-ASA than the newer preparations, which require pH changes or dissolution of microspheres. The pH profile of the gastrointestinal tract was reported in normal volunteers in the 1960s. Extrapolating from normal volunteers to patients with ulcerative colitis who have altered intestinal transit might be unrealistic. Radiotelemetric mapping of the pH of luminal contents showed differences (P < 0.02) in the pH of the right colon of patients with ulcerative colitis (pH 4.7) compared with controls (pH 6.7). Similar differences were noted in patients with disease in remission [77]. Thus, 5-ASA preparations that require specific alterations in pH for release might function in a suboptimal manner in patients with ulcerative colitis.

Although side effects tended to be reported more frequently in sulfasalazine-treated patients compared with those receiving 5-ASA, the newer preparations can also provoke adverse reactions. A proportion of patients previously thought to be sulfapyridine sensitive are 5-ASA sensitive. The seminal fluid abnormalities (oligospermia, reduced sperm motility, and abnormal forms) associated with sulfasalazine are, however, related to the sulfapyridine molecule and can be reversed with 5-ASA substitution [78]. Many of the patients who participated in the accepted studies that used sulfasalazine as one of the treatment arms had often taken sulfasalazine in the past, a result that might have biased the study cohort toward patients who could tolerate sulfasalazine.

Only a few validated clinical, endoscopic, and histologic indices are available to assess therapeutic response in ulcerative colitis. Our approach was to focus on clinical remission for short-term studies and maintenance of remission for long-term studies. This lack of consistency in indices might have obscured the detection of significant differences.

Our meta-analysis of trials of 5-ASA therapy for ulcerative colitis showed that none of the newer preparations was superior to sulfasalazine in the treatment of active ulcerative colitis or for maintenance of remission of ulcerative colitis. In Canada, the cost of the newer 5-ASA preparations is approximately three to four times that of sulfasalazine. For the sulfasalazine-sensitive patient, 5-ASA preparations remain an important advance. However, given the cost of the newer preparations, clinicians might reserve their general use for patients who do not initially respond to sulfasalazine or for men who are concerned about infertility.

Abbreviation

5-ASA: 5-aminosalicylic acid

Author and Article Information

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From the University of Calgary, Calgary, Alberta, Canada.
Requests for Reprints: Lloyd Sutherland, MD, Room 1751, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1.
Grant Support: In part by a grant from the Calgary Gastroenterology Research and Education Foundation. Dr. May was a Canadian Association of Gastroenterology/Merck Frosst Canada Research Fellow.

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