Tratamiento por vía oral con ácido 5‐aminosalicílico para mantener la remisión de la colitis ulcerosa
Resumen
Antecedentes
Las preparaciones orales de ácido 5‐aminosalicílico (5‐ASA, también conocido como mesalazina) tienen como objetivo evitar los efectos adversos de la sulfasalazina (SASP) y mantener al mismo tiempo sus beneficios terapéuticos. En una versión anterior de esta revisión, se encontró que los fármacos 5‐ASA eran más efectivos que el placebo para el mantenimiento de la remisión de la colitis ulcerosa (CU), pero tenían una inferioridad terapéutica significativa en relación con la SASP. En esta versión, se ha repetido la búsqueda para actualizar la revisión.
Objetivos
Evaluar la eficacia, la respuesta a la dosis y la seguridad del 5‐ASA por vía oral en comparación con el placebo, la SASP o los comparadores de 5‐ASA para el mantenimiento de la remisión en la colitis ulcerosa (CU) inactiva, y comparar la eficacia y la seguridad de la dosis única diaria de 5‐ASA por vía oral con los regímenes de dosis convencionales (dos o tres veces al día).
Métodos de búsqueda
Se realizó una búsqueda bibliográfica de estudios el 11 de junio de 2019 en MEDLINE, Embase y la Biblioteca Cochrane. Además, se hicieron búsquedas en artículos de revisión y en actas de congresos.
Criterios de selección
Se incluyeron ensayos controlados aleatorizados con una duración de tratamiento mínima de seis meses. Se consideraron estudios de la terapia con 5‐ASA por vía oral para el tratamiento de participantes con CU inactiva en comparación con placebo, SASP u otras formulaciones de 5‐ASA. También se incluyeron estudios que compararon el tratamiento con una dosis única diaria de 5‐ASA con la dosis convencional y los estudios de rango de dosis de 5‐ASA.
Obtención y análisis de los datos
Se utilizaron los procedimientos metodológicos estándares previstos por Cochrane. El desenlace principal fue el fracaso en el mantenimiento de la remisión clínica o endoscópica. Los desenlaces secundarios fueron la adherencia, los eventos adversos (EA), los eventos adversos graves (EAG), los abandonos debido a los eventos adversos y los abandonos o las exclusiones después del ingreso. Los ensayos se separaron en cinco grupos de comparación: 5‐ASA versus placebo, 5‐ASA versus SASP, dosis única diaria versus dosis convencional, 5‐ASA (balsalazida, Pentasa y olsalazina) versus formulación comparativa de 5‐ASA (Asacol y Salofalk), y rango de dosis de 5‐ASA. Para cada desenlace se calculó el riesgo relativo (RR) y los intervalos de confianza (IC) del 95%. Los datos se analizaron por intención de tratar y se utilizó GRADE para evaluar la certeza general de la evidencia.
Resultados principales
En la búsqueda se identificaron 44 ECA (9967 participantes). La mayoría de los estudios presentó bajo riesgo de sesgo. Diez estudios tuvieron un riesgo de sesgo alto. Siete de estos estudios tuvieron cegamiento simple y tres fueron abiertos.
El 5‐ASA es más efectivo que el placebo para el mantenimiento de la remisión clínica o endoscópica. Aproximadamente el 37% (335/907) de los participantes en el grupo de 5‐ASA tuvo recaída a los seis a 12 meses en comparación con el 55% (355/648) de los participantes en el grupo placebo (RR 0,68, IC del 95%: 0,61 a 0,76; ocho estudios; 1555 participantes; evidencia de certeza alta). No se informó de la adherencia a la medicación de estudio en el caso de esta comparación. Se informaron EAG en el 1% (6/550) de los participantes del grupo de 5‐ASA en comparación con el 2% (5/276) de los participantes del grupo de placebo a los seis a 12 meses (RR 0,60; IC del 95%: 0,19 a 1,84; tres estudios, 826 participantes; evidencia de certeza baja). Es probable que haya poca o ninguna diferencia en los EA a los seis a 12 meses de seguimiento (RR 0,93; IC del 95%: 0,73 a 1,18; cinco estudios; 1132 participantes; evidencia de certeza moderada).
La SASP es más efectiva que el 5‐ASA para el mantenimiento de la remisión. Aproximadamente el 48% (416/871) de los participantes en el grupo de 5‐ASA tuvo recaída a los seis a 18 meses en comparación con el 43% (336/784) de los participantes en el grupo de SASP (RR 1,14, IC del 95%: 1,03 a 1,27; 12 estudios; 1655 participantes; evidencia de certeza alta). No se informó de la adherencia a la medicación de estudio ni de los EAG de esta comparación. Es probable que haya poca o ninguna diferencia en los EA a los seis a 12 meses de seguimiento (RR 1,07; IC del 95%: 0,82 a 1,40; siete estudios; 1138 participantes; evidencia de certeza moderada).
Hay poca o ninguna diferencia en las tasas de remisión clínica o endoscópica entre el 5‐ASA en dosis única diaria y la dosis convencional. Aproximadamente el 37% (717/1939) de los participantes en el grupo de dosis única diaria tuvo recaída en los 12 meses siguientes en comparación con el 39% (770/1971) de los participantes en el grupo de la dosis convencional (RR 0,94; IC del 95%: 0,88 a 1,01; diez estudios; 3910 participantes; evidencia de certeza alta). Probablemente haya una diferencia escasa o nula en las tasas de adherencia a la medicación. Alrededor del 10% (106/1152) de los participantes en el grupo de dosis única diaria no se adhirió a su régimen de medicación en comparación con el 8% (84/1154) de los participantes en el grupo de dosis convencional (RR 1,18; IC del 95%: 0,72 a 1,93; nueve estudios; 2306 participantes; evidencia de certeza moderada). Alrededor del 3% (41/1587) de los participantes en el grupo de dosis única diaria experimentaron un EAG en comparación con el 2% (35/1609) de los participantes en el grupo de dosis convencional a los seis a 12 meses (RR 1,20; IC del 95%: 0,77 a 1,87; evidencia de certeza moderada). Hay poca o ninguna diferencia en la incidencia de EA a los seis a 13 meses de seguimiento (RR 0,98; IC del 95%: 0,92 a 1,04; ocho estudios; 3497 participantes; evidencia de certeza alta).
Puede haber poca o ninguna diferencia en la eficacia entre las diferentes formulaciones de 5‐ASA. Sobre el 44% (158/358) de los participantes en el grupo de 5‐ASA tuvo recaída a los seis a 18 meses en comparación con el 41% (142/349) de los participantes en el grupo de comparación 5‐ASA (RR. 1,08; IC del 95%: 0,91 a 1,28; seis estudios; 707 participantes; evidencia de certeza baja).
Conclusiones de los autores
Hay evidencia de certeza alta de que el 5‐ASA es mejor que el placebo para la terapia de mantenimiento en la CU. Hay evidencia de certeza alta de que el 5‐ASA es inferior al SASP. Probablemente hay poca o ninguna diferencia entre el 5‐ASA y el placebo, y el 5‐ASA y la SASP en los EA comúnmente reportados como flatulencia, dolor abdominal, náuseas, diarrea, dolor de cabeza y dispepsia. El 5‐ASA por vía oral administrado en dosis única diaria presenta un perfil de efectos beneficiosos y perjudiciales similar al de la dosis convencional para el mantenimiento de la remisión de la CU inactiva.
PICO
Resumen en términos sencillos
Compuestos de ácido 5‐aminosalicílico para mantener la remisión de la colitis ulcerosa
¿Cuál era el objetivo de esta revisión?
El objetivo de esta revisión Cochrane fue averiguar si el ácido 5‐aminosalicílico oral (también conocido como mesalazina) ayuda a mantener la remisión y a prevenir la recaída en personas con colitis ulcerosa. La colitis ulcerosa es una enfermedad inflamatoria del intestino que provoca una inflamación duradera del colon. Algunos síntomas comunes incluyen diarrea con sangre, dolor abdominal y rectal, pérdida de peso, fatiga y fiebre. Los autores de la revisión recopilaron y analizaron todos los estudios relevantes para responder a esta pregunta y se encontraron 44 estudios.
¿Cuál es el grado de actualización de esta revisión?
Los autores de la revisión buscaron estudios publicados hasta junio de 2019.
¿Qué se estudió en la revisión?
Los investigadores examinaron si el ácido 5‐aminosalicílico por vía oral era mejor que un placebo (un medicamento falso), otras formulaciones de ácido 5‐aminosalicílico de comparación, la sulfasalazina, diferentes dosis de ácido 5‐aminosalicílico por vía oral y una dosis diaria en comparación con la dosis convencional en personas con colitis ulcerosa. Los desenlaces incluían la remisión clínica o endoscópica (en la que se introduce un tubo largo y delgado directamente en el intestino), el cumplimiento del régimen de medicación y los efectos secundarios de la medicación.
¿Cuáles son los principales resultados de la revisión?
Los autores de la revisión encontraron 44 estudios pertinentes (9967 participantes). Los estudios compararon medicación de ácido 5‐aminosalicílico por vía oral con placebo, otras formulaciones de ácido 5‐aminosalicílico de comparación, la sulfasalazina, diferentes dosis de ácido 5‐aminosalicílico por vía oral y una dosis diaria en comparación con la dosis convencional.
Ocho estudios (1555 participantes) evaluaron la eficacia del ácido 5‐aminosalicílico por vía oral en comparación con el placebo. En los estudios se determinó que el ácido 5‐aminosalicílico por vía oral era más efectivo que el placebo para mantener la remisión clínica o endoscópica (evidencia de certeza alta). Doce estudios (1655 participantes) evaluaron la efectividad de la sulfasalazina en comparación con el ácido 5‐aminosalicílico. Los estudios determinaron que la sulfasalazina era ligeramente más efectiva en comparación con el ácido 5‐aminosalicílico (evidencia de certeza alta). Diez estudios (3910 participantes) evaluaron la efectividad de la dosis única diaria en comparación con la dosis convencional (dos veces al día). Los estudios encontraron que probablemente no hubo diferencias entre los grupos para mantener la remisión clínica o endoscópica (evidencia de certeza moderada). También se hizo un análisis adicional de la adherencia a la medicación de estudio en dosis única diaria frente a la convencional. Los resultados mostraron que probablemente no hubo diferencias en la adherencia a la medicación entre los dos grupos de dosis (evidencia de certeza moderada). Seis estudios (1781 participantes) evaluaron el ácido 5‐aminosalicílico por vía oral (por ejemplo, balsalazida, Pentasa y olsalazina) en comparación con otras formulaciones de ácido 5‐aminosalicílico (por ejemplo, Asacol y Salofalk). Los estudios encontraron que probablemente no había diferencias en la remisión clínica o endoscópica entre el ácido 5‐aminosalicílico y los grupos de comparación (evidencia de certeza baja).
Es probable que haya poca o ninguna evidencia de una diferencia en los efectos secundarios comúnmente comunicados entre el ácido 5‐aminosalicílico y cualquiera de los comparadores. Los efectos secundarios notificados con más frecuencia incluyeron flatulencias, dolor abdominal, náuseas, diarrea, cefalea, dispepsia (indigestión) y nasofaringitis (inflamación de los conductos nasales).
Authors' conclusions
Summary of findings
| Oral 5‐ASA vs placebo for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent UC | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 6–12 months | 584 per 1000 | 373 per 1000 | RR 0.68 | 1555 | ⊕⊕⊕⊕ | Clinical remission defined using the revised SDAI (rectal bleeding = 0, mucosal appearance ≤ 2). |
| Failure to adhere to study medication | Outcome not reported. | Not reported. | ||||
| Adverse events Follow‐up: 6–12 months | 400 per 1000 | 372 per 1000 | RR 0.93 | 1132 | ⊕⊕⊕⊝ | Common adverse events included headache, nausea, abdominal pain, dyspepsia, bloating, influenza syndrome, rhinitis, diarrhea, and nasopharyngitis. |
| Serious adverse events Follow‐up: 6–12 months | 18 per 1000 | 11 per 1000 (3 to 33) | RR 0.60 (0.19 to 1.84) | 826 (3 studies) | ⊕⊕⊝⊝ | Serious adverse events included UC aggravation, acute pancreatitis, moderate ventricular dysfunction, intestinal obstruction, and esophagitis. |
| Withdrawal due to adverse event Follow‐up: 6–12 months | 45 per 1000 | 55 per 1000 | RR 1.22 | 1454 | ⊕⊕⊕⊝ | Common adverse events leading to withdrawal included UC aggravation diarrhea, headache, and paresthesia. |
| Exclusion/withdrawal after entry Follow‐up: 6–12 months | 185 per 1000 | 209 per 1000 (162 to 266) | RR 1.13 (0.88 to 1.44) | 1074 (5 studies) | ⊕⊕⊕⊝ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; RR: risk ratio; SDAI: Sutherland Disease Activity Index; UC: ulcerative colitis. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to serious imprecision (478 events). | ||||||
| Oral 5‐ASA vs SASP for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| SASP | Oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 6–18 months | 429 per 1000 | 489 per 1000 | RR 1.14 | 1655 | ⊕⊕⊕⊕ | Clinical or endoscopic remission defined as the absence of colitis symptoms together with an absence of inflammation on sigmoidoscopy. |
| Failure to adhere to study medication | Outcome not reported. | Not reported. | ||||
| Adverse event Follow‐up: 6–18 months | 158 per 1000 | 170 per 1000 | RR 1.07 | 1138 | ⊕⊕⊕⊝ | Commonly reported adverse events in the SASP‐controlled trials included: headache, anorexia or appetite loss, nausea, vomiting, abdominal pain, dyspepsia, excessive flatus, bloating, urticaria, and rash. |
| Serious adverse events | Outcome not reported. | Not reported. | ||||
| Withdrawal due to adverse event Follow‐up: 6–18 months | 54 per 1000 | 69 per 1000 | RR 1.27 | 1585 | ⊕⊕⊕⊝ | Common adverse events leading to withdrawal included diarrhea, abdominal pain, indigestion, and rash. |
| Exclusion/withdrawal after entry Follow‐up: 6–18 months | 154 per 1000 | 200 per 1000 (160 to 251) | RR 1.30 (1.04 to 1.63) | 1497 (9 studies) | ⊕⊕⊕⊝ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; RR: risk ratio; SASP: sulfasalazine. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to imprecision (182 events). | ||||||
| Once‐daily dosing vs conventional dosing for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent UC | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Conventionally dosed oral 5‐ASA | OD oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 12–13 months | 391 per 1000 | 367 per 1000 | RR 0.94 | 3910 | ⊕⊕⊕⊕ | Clinical or endoscopic remission defined as a mucosal score of 0 or 1 (endoscopic remission), or a bloody stool score of 0 and an UC‐DAI < 2/Simple Clinical Colitis Activity Index score of ≤ 2 points (clinical remission). |
| Failure to adhere to study medication regimen Follow‐up: 6–13 months | 73 per 1000 | 86 per 1000 | RR 1.18 | 2306 | ⊕⊕⊕⊝ | Adherence to medication regimen calculated using objective data (pill count or pharmacy data) in 6/9 studies in the analysis. 2 studies used participant self‐report to calculate adherence and 1 study did not describe how adherence was assessed. |
| Adverse event Follow‐up: 6–13 months | 490 per 1000 | 481 per 1000 | RR 0.98 | 3497 | ⊕⊕⊕⊕ | Common adverse events included flatulence, dyspepsia, abdominal pain, nausea, diarrhea, headache, nasopharyngitis, inflammation of the upper respiratory tract, gastroenteritis. dental caries, and worsening of UC. |
| Serious adverse events Follow‐up: 6–13 months | 22 per 1000 | 26 per 1000 (17 to 41) | RR 1.20 (0.77 to 1.87) | 3196 (7 studies) | ⊕⊕⊕⊝ | Serious adverse events included UC aggravation, acute pancreatitis, anal fistula, pneumonia, melena, nephrolithiasis, and hypersensitivity pneumonitis. |
| Withdrawal due to adverse events Follow‐up: 6–13 months | 14 per 1000 | 17 per 1000 | RR 1.18 | 4340 | ⊕⊝⊝⊝ | Adverse events leading to withdrawal included UC aggravation, flatulence, nausea, and abdominal distension. |
| Exclusion/withdrawal after entry Follow‐up: 6–13 months | 150 per 1000 | 148 per 1000 (127 to 172) | RR 0.99 (0.85 to 1.15) | 3737 (7 studies) | ⊕⊕⊕⊕ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; OD: once daily; RR: risk ratio; SDAI: Sutherland Disease Activity Index; UC: ulcerative colitis; UC‐DAI: Ulcerative Colitis Disease Activity Index. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to imprecision (190 events). | ||||||
| Oral 5‐ASA vs comparator 5‐ASA formulation for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent UC | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Comparator Oral 5‐ASA | Oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 6–18 months | 407 per 1000 | 439 per 1000 | RR 1.08 | 707 | ⊕⊕⊝⊝ | Clinical or endoscopic remission was defined as either the Harvey Bradshaw Index (score < 3) and by a sigmoidoscopy (score 0–1) or the absence of symptoms or the presence of only mild symptoms. |
| Failure to adhere to study medication regimen | Outcome not reported. | Not reported. | ||||
| Adverse event Follow‐up: 6–12 months | 686 per 1000 | 645 per 1000 | RR 0.94 | 357 | ⊕⊕⊝⊝ | Common adverse events included dyspepsia, abdominal pain, nausea, distension, diarrhea, headache, nasopharyngitis or respiratory infections, influenza‐like disorder, and rash. |
| Serious adverse events Follow‐up: 12 months | 109 per 1000 | 61 per 1000 (15 to 24) | RR 0.56 (0.14 to 2.22) | 95 (1 study) | ⊕⊕⊝⊝ | Serious adverse events reported included urinary tract infection, severe complication of UC, cardiac arrest, ischemic heart, fracture of the scaphoid, and spigelian hernia. |
| Withdrawal due to adverse events Follow‐up: 6–12 months | 44 per 1000 | 56 per 1000 | RR 1.25 | 457 | ⊕⊝⊝⊝ | Common adverse events leading to withdrawal included headache, lethargy, hypertension, malaise, and abdominal pain. |
| Exclusion/withdrawal after entry Follow‐up: 6–12 months | 222 per 1000 | 273 per 1000 (200 to 378) | RR 1.23 (0.90 to 1.70) | 457 (5 studies) | ⊕⊕⊕⊝ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; OD: once daily; RR: risk ratio; SDAI: Sutherland Disease Activity Index; UC: ulcerative colitis. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to serious imprecision (300 events). | ||||||
Background
Description of the condition
Ulcerative colitis (UC) is an inflammatory bowel condition that results in long‐lasting inflammation of the colon. Some common symptoms of UC include diarrhea, abdominal and rectal pain, weight loss and fatigue. In addition to these symptoms, approximately 6% to 47% of patients also experience extraintestinal manifestations affecting the eyes, joints, liver, and skin. These manifestations may include arthritis, uveitis, oral ulcers, and primary sclerosing cholangitis (Rothfuss 2006). The pathogenesis of UC is unknown; however, there are genetic and environmental factors that have been correlated with the increased risk. UC is more common in the industrialized world, especially in North America and Western Europe. The overall worldwide incidence is 1.2 to 20.3 cases per 100,000 people per year, with a prevalence of 7.6 to 245 cases per 100,000 people per year (Danese 2011; Loftus 2004). In North America, the prevalence of UC ranges from 120 to 250 cases per 100,000 people and the incidence ranges from 8 to 20 cases per 100,000 people (Loftus 2004).
Treatments for UC may include biological therapies (adalimumab, infliximab, vedolizumab, golimumab, ustekinumab), corticosteroids, azathioprine or 6‐mercaptopurine, and 5‐aminosalicylic acids (5‐ASA; also known as mesalazine or mesalamine). For people with mild‐to‐moderate UC, 5‐ASAs and corticosteroids are the standard treatment for induction of remission. This is followed by thiopurines, anti‐tumor necrosis factor (anti‐TNF) drugs, or adhesion molecule inhibitors for moderate‐to‐severe UC (Feuerstein 2014).
Description of the intervention
The successful management of UC was greatly facilitated after the introduction of sulfasalazine (SASP) by Svartz (Svartz 1942). SASP is composed of 5‐ASA linked to sulfapyridine via a diazo bond. This bond is readily cleaved by bacterial azoreductases in the colon to yield the two components (Peppercorn 1972). Of these, 5‐ASA is the therapeutically active component, while sulfapyridine, which is primarily absorbed into systemic circulation, is assumed to function solely as a carrier molecule (Azad Khan 1977; Klotz 1980; Van Hees 1980).
How the intervention might work
Administration of unbound or uncoated 5‐ASA revealed that it was readily absorbed in the upper jejunum and was unable to reach the colon in therapeutic concentrations (Myers 1987; Nielsen 1983; Schroeder 1972). Ingested SASP largely resists such premature absorption and thus is able to serve as a delivery system that transports 5‐ASA to the affected regions of the lower intestinal tract (Schroeder 1972). While corticosteroid therapy is more effective in the treatment of severe UC (Truelove 1955; Truelove 1959), the use of SASP in maintaining remission has been well established (Misiewitz 1965).
Despite its benefits, up to 30% of people receiving SASP have reported adverse effects (AE) (Nielsen 1982). It was concluded that many were due to the sulfapyridine moiety, especially those effects found to be dose‐dependent (Das 1973; Myers 1987). This discovery spawned more than a decade of research aimed at finding alternative 5‐ASA delivery systems.
Asacol® (Proctor and Gamble) consists of a pellet of 5‐ASA destined for release in the terminal ileum or colon due to a coating known as Eudragit‐S, a resin that dissolves at a pH greater than 7 (Dew 1982a). Claversal® or Mesasal® (GlaxoSmithKline), Salofalk® (Axcan Pharma, Falk Foundation), and Rowasa® (Reid‐Rowell) are similar delayed‐release preparations of 5‐ASA pellets coated with Eudragit L, a resin that dissolves at a pH greater than 6 (the approximate pH of the ileum/colon) (Hardy 1987; Myers 1987). Pentasa® (Marion‐Merrell‐Dow) is a microsphere formulation that consists of 5‐ASA microgranules enclosed within a semi‐permeable membrane of ethylcellulose. It is designed for controlled release that begins in the duodenum and continues into the affected regions of the lower bowel (Rasmussen 1982). Olsalazine or Dipentum® (Pharmacia & Upjohn) consists of two 5‐ASA molecules linked by a diazo bond (Staerk Laursen 1990; Willoughby 1982). Other formulations, such as benzalazine and balsalazide, are composed of 5‐ASA molecules azo‐bonded to various benzoic acid derivatives (Chan 1983; Fleig 1988). Like SASP, these compounds are poorly absorbed in the upper digestive tract but are readily metabolized by the intestinal flora in the lower bowel. MMX mesalamine (Lialdaa® or Mezavanta®) uses Multi Matrix System (MMX) technology to delay and extend delivery of active drug throughout the colon (Kamm 2008).
The newer 5‐ASA preparations were intended to avoid the AEs of SASP while maintaining its therapeutic benefits. These drugs are more costly, however, and still cause AEs in some patients (Rao 1987). The efficacy and safety of the 5‐ASA preparations have been evaluated in numerous clinical trials that have often lacked sufficient statistical power to arrive at definitive conclusions. In an earlier meta‐analysis, Sutherland 1993 found that the newer 5‐ASA drugs were no more effective than SASP for maintenance of remission in UC. This systematic review is an update of the Cochrane Review published in 2012 (Feagan 2012). We proceeded with this updated review, in accordance with the format of Cochrane, to include the more recent studies as well as to evaluate the effectiveness, dose‐responsiveness, and safety of the 5‐ASA preparations in terms of more precise outcome measures.
Many patients are non‐adherent with conventional multi‐dose (two or three times daily) treatment regimens, which may result in reduced efficacy and can lead to an increased risk of relapse in people with quiescent disease (Kane 2001; Kane 2003a), poor long‐term prognosis (Kane 2008a), and increased costs of care (Beaulieu 2009; Kane 2008a). Poor adherence may be particularly problematic in quiescent disease (Kane 2001; Kane 2003a), since patients lack continuing symptoms that incentivize them to take medication. Although multiple factors influence medication adherence in people with UC, it is commonly believed that a high pill burden and multi‐dose regimens are major determinants (Ediger 2007; Kane 2008a). Accordingly, it is reasonable to hypothesize that once‐daily dosing of 5‐ASA might improve both adherence with maintenance therapy and outcomes.
Why it is important to do this review
This review was performed to assess the evidence supporting the use of oral 5‐ASA for the maintenance of remission in people with UC. The efficacy and safety of oral 5‐ASA compared to placebo, oral 5‐ASA compared to different formulations, and once‐daily compared to conventional dosing for the treatment of UC. Many of these trials were small and lacked sufficient statistical power to arrive at definitive conclusions. This systematic review is an update of a previously published Cochrane Review and includes three new studies (Gordon 2016; Park 2019; Suzuki 2017).
Objectives
To assess the efficacy, dose‐responsiveness, and safety of oral 5‐ASA compared to placebo, SASP, or 5‐ASA comparators for maintenance of remission in quiescent UC and to compare the efficacy and safety of once‐daily dosing of oral 5‐ASA with conventional (two or three times daily) dosing regimens.
Methods
Criteria for considering studies for this review
Types of studies
Prospective, randomized controlled trials of parallel design, with a minimum treatment duration of six months.
Types of participants
Participants of any age with mild‐to‐moderate UC in remission as defined by Truelove and Witts (Truelove 1955).
Types of interventions
We included trials of oral 5‐ASA therapy for treatment of participants with UC in remission compared with placebo, SASP, or other formulations of 5‐ASA. We also considered studies that compared once‐daily 5‐ASA treatment with conventional dosing of 5‐ASA (two or three times daily) and 5‐ASA dose‐ranging studies.
Types of outcome measures
Outcome measures included endoscopic or clinical relapse, or early withdrawal, as defined by the authors of each study.
Primary outcomes
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Endoscopic or clinical relapse as defined by the authors of each study.
Secondary outcomes
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Adherence with medication regimen.
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Adverse events (AE).
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Serious adverse events (SAE).
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Withdrawal due to AEs.
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Exclusion of withdrawal after entry.
Search methods for identification of studies
Electronic searches
We searched MEDLINE, Embase, the Cochrane library (CENTRAL), the Cochrane IBD Specialized Register, and clinicaltrials.gov from inception to 11 June 2019. We applied no language or document type restrictions. The search strategy is listed in Appendix 1.
Searching other resources
We searched review articles and conference abstracts to identify additional studies.
Data collection and analysis
Selection of studies
Two review authors (AM and TN) independently selected relevant studies for analysis based on the prespecified inclusion criteria. We discussed disagreements between review authors and reached agreement by consensus. When necessary, we contacted the original authors to clarify outcomes and trial methodology.
Data extraction and management
Two review authors (AM and TN) independently extracted data using a standard data extraction form. We recorded results using an intention‐to‐treat (ITT) basis and settled any discrepancies between review authors by consensus. We extracted baseline characteristics (sex, age, disease location, disease duration), intervention type (dose, administration), comparator (no intervention, placebo, active comparator), and prespecified primary and secondary outcomes.
Assessment of risk of bias in included studies
Two review authors (AM and TN) independently assessed the risk of bias in the included studies using the Cochrane 'Risk of bias' tool (Higgins 2011a). Factors assessed included:
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sequence generation (i.e. was the allocation sequence adequately generated?);
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allocation sequence concealment (i.e. was allocation adequately concealed?);
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blinding (i.e. was knowledge of the allocated intervention adequately prevented during the study?);
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incomplete outcome data (i.e. were incomplete outcome data adequately addressed?);
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selective outcome reporting (i.e. are reports of the study free of suggestion of selective outcome reporting?); and
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other potential sources of bias (i.e. was the study apparently free of other problems that could put it at a high risk of bias?).
A judgement of 'yes' indicated low risk of bias, 'no' indicated high risk of bias, and 'unclear' indicated unclear or unknown risk of bias. We resolved disagreements by consensus. We contacted study authors when there was insufficient information to determine risk of bias.
Measures of treatment effect
For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). We pooled the results for each comparison group to determine the RR and 95% CI for each outcome resulting from 5‐ASA therapy relative to placebo, SASP, or 5‐ASA comparator; and once‐daily 5‐ASA therapy relative to conventional dosing. We used a fixed‐effect model. We pooled studies for analysis if participants, outcomes, and interventions were similar (determined by consensus among authors). We pooled studies comparing 5‐ASA formulations for analysis if they compared equimolar doses of oral 5‐ASA. For continuous outcomes, we planned to calculate the mean difference (MD) if studies used the same scale, or standardized mean difference (SMD) if studies used different scales, both with 95% CI.
Unit of analysis issues
For trials with multiple arms (e.g. different dose groups), we divided the placebo group across subgroups so that independent comparisons could be performed between each subgroup and the split placebo group (Higgins 2011b). To avoid potential carry‐over effects, we only used data from before the first cross‐over for any included cross‐over studies. For outcomes that were measured at different time points, we determined the appropriate fixed intervals for follow‐up (Higgins 2011b). For recurring events (i.e. AEs), we used the proportion of participants who had at least one event for analysis. There were no cluster randomized trials.
Dealing with missing data
We analyzed missing dichotomous outcomes according to the ITT principle. Participants with missing data were assumed to be treatment failures. Alternatively, for continuous outcomes, we used the number of participants who completed the trial and did not impute any missing variables.
Assessment of heterogeneity
We assessed the presence of heterogeneity among studies using the Chi² test (a P value of 0.10 was statistically significant) and the I² statistic (Higgins 2003). If there was statistically significant heterogeneity, we calculated the RR and 95% CI using a random‐effects model. We did not pool data in a meta‐analysis if there was a high degree of heterogeneity (e.g. I² greater than 75%).
Assessment of reporting biases
We compared the outcomes listed in the study protocols to the outcomes listed in the final manuscripts. However, if we could not locate the protocol, we compared the outcomes listed in the methods section to the outcomes in the results section. If there was a sufficient number of studies included (i.e. more than 10) in the pooled analyses, we planned to use a funnel plot to investigate a potential publication bias.
Data synthesis
Trials made five comparisons: 5‐ASA versus placebo, 5‐ASA versus SASP, once‐daily dosing versus conventional dosing, 5‐ASA versus comparator 5‐ASA, and 5‐ASA dose‐ranging. We pooled data from studies where the intervention, participant groups, and outcomes were similar. We pooled the RR and 95% CI for dichotomous outcomes and the MD or SMD and corresponding 95% CI for continuous outcomes.
Subgroup analysis and investigation of heterogeneity
We performed the following subgroup analyses.
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Once‐daily versus conventional dosing studies subgrouped by formulation.
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5‐ASA‐controlled trials subgrouped by common 5‐ASA comparators (e.g. Asacol, Claversal, Salofalk, and Pentasa).
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Dose‐ranging studies subgrouped by 5‐ASA formulation.
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Subgrouped according to the specific 5‐ASA preparation for those outcomes for which there were two or more studies that used a similar drug.
Sensitivity analysis
We conducted sensitivity analyses as appropriate to investigate heterogeneity. We also conducted sensitivity analyses excluding studies with a high risk of bias. All statistical analyses were performed using the Cochrane Review Manager 5 software package (Review Manager 2014).
'Summary of findings' tables
We used the GRADE approach for rating the overall certainty of the evidence for the primary outcomes and selected secondary outcomes of interest. Randomized trials start as high‐certainty evidence, but may be downgraded due to:
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limitations in design and implementation (risk of bias);
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indirectness of evidence;
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inconsistency (unexplained heterogeneity);
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imprecision (sparse data); and
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reporting bias (publication bias).
The overall certainty of the evidence for each outcome was determined after considering each of these elements, and categorized as high certainty (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate certainty (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low certainty (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); and very‐low certainty (i.e. we are very uncertain about the estimate) (Guyatt 2008; Schünemann 2011).
For the 'Summary of findings' tables, we included the following outcomes: endoscopic or clinical relapse, failure to adhere with study medication, at least one AEs, at least one SAEs, withdrawal due to AEs and exclusion/withdrawal after entry.
Results
Description of studies
Results of the search
The literature search conducted on 11 June 2019 identified 3331 studies. We identified 20 additional studies through searching of references. After removal of duplicates, 2321 reports remained for review of titles and abstracts. After reviewing the titles and abstracts of these studies, we selected 132 reports of oral 5‐ASA maintenance treatment for quiescent UC for full‐text review (Figure 1).
Study flow diagram.
Included studies
We included 88 reports of 44 studies involving 9967 participants (Andreoli 1987; Ardizzone 1995; Ardizzone 1999; Courtney 1992; D'Haens 2012; Deventer 2001; Dew 1983; Dignass 2009a; Fockens 1995; Giaffer 1992a; Gordon 2016; Green 1992; Green 1998; Hanauer 1996; Hawkey 1997; Hawthorne 2012; Ireland 1988a; Ito 2010; Kamm 2008; Kane 2003b; Kane 2008b; Kiilerich 1992; Kruis 1995; Kruis 2001; Kruis 2011; Lichtenstein 2010; Mahmud 2002; McIntyre 1988; Miner 1995; Mulder 1988; Nilsson 1995; Paoluzi 2005; Park 2019; Pica 2012; Prantera 2009; Rijk 1992; Riley 1988; Rutgeerts 1989; Sandberg‐Gertzen 1986; Sandborn 2010; Suzuki 2017; Travis 1994; Watanabe 2013; Wright 1993) (see Characteristics of included studies table).
Eight studies were placebo‐controlled (Ardizzone 1999; Gordon 2016; Hanauer 1996; Hawkey 1997; Lichtenstein 2010; Miner 1995; Sandberg‐Gertzen 1986; Wright 1993). Twelve studies compared 5‐ASA to SASP (Andreoli 1987; Ardizzone 1995; Dew 1983; Ireland 1988a; Kiilerich 1992; Kruis 1995; McIntyre 1988; Mulder 1988; Nilsson 1995; Rijk 1992; Riley 1988; Rutgeerts 1989). Twelve studies were maintenance of remission studies comparing once‐daily dosing of 5‐ASA with conventional dosing (D'Haens 2012; Dignass 2009a; Hawthorne 2012; Kamm 2008; Kane 2003b; Kane 2008b; Kruis 2011; Park 2019; Prantera 2009; Sandborn 2010; Suzuki 2017; Watanabe 2013). Six studies compared the efficacy and safety of various formulations of oral 5‐ASA to other formulations of oral 5‐ASA for maintenance treatment (Courtney 1992; Deventer 2001; Green 1998; Ito 2010; Kruis 2001; Mahmud 2002). Ten trials were dose‐ranging studies of oral 5‐ASA (Deventer 2001; Fockens 1995; Giaffer 1992a; Green 1992; Hanauer 1996; Kruis 2001; Kruis 2011; Paoluzi 2005; Pica 2012; Travis 1994). Six studies were formal non‐inferiority studies (D'Haens 2012; Dignass 2009a; Hawthorne 2012; Ito 2010; Sandborn 2010; Watanabe 2013).
Excluded studies
We excluded 39 reports with reasons (see Characteristics of excluded studies table).
Risk of bias in included studies
A summary of the risk of bias assessment is provided in Figure 2. Most of the included studies were of high methodological quality. Ten studies were at high risk of bias.
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
Allocation
Nineteen studies did not describe methods used for allocation concealment and were rated as unclear for this item (Andreoli 1987; Ardizzone 1999; Ardizzone 1995; Courtney 1992; Deventer 2001; Dew 1983; Fockens 1995; Giaffer 1992a; Gordon 2016; Green 1992; Green 1998; Hawthorne 2012; Kruis 2001; Lichtenstein 2010; Mahmud 2002; Paoluzi 2005; Pica 2012; Travis 1994; Watanabe 2013). The remaining studies were at low risk of allocation bias.
Thirty of 43 included studies did not describe the method used for randomization and were rated as unclear for this item (Ardizzone 1995; Ardizzone 1999; D'Haens 2012; Deventer 2001; Dew 1983; Dignass 2009a; Giaffer 1992a; Gordon 2016; Green 1992; Green 1998; Hawkey 1997; Hawthorne 2012; Ireland 1988a; Kamm 2008; Kruis 2011; Lichtenstein 2010; McIntyre 1988; Miner 1995; Mulder 1988; Nilsson 1995; Paoluzi 2005; Pica 2012; Rijk 1992; Riley 1988; Rutgeerts 1989; Sandberg‐Gertzen 1986; Sandborn 2010; Travis 1994; Watanabe 2013; Wright 1993). The remaining studies were at low risk of randomization bias.
Blinding
Seven studies were single‐blind with a blinded investigator assessing outcomes (Courtney 1992; Deventer 2001; Dignass 2009a; Hawthorne 2012; Kane 2003b; Kane 2008b; Sandborn 2010). Three studies were open‐label and investigators and participants were not blinded to treatment assignment (Kamm 2008; Mahmud 2002; Pica 2012). However, two open‐label studies (Kamm 2008; Mahmud 2002), and four of seven single‐blind studies (Courtney 1992; Dignass 2009a; Hawthorne 2012; Kane 2008b), utilized investigator‐performed endoscopy as an endpoint, which may protect against bias provided the endoscopist is blinded. The methods used for blinding were not described in one study and this study was rated as unclear (Green 1992). The remaining studies were at low risk of performance and detection bias.
Incomplete outcome data
Thirteen studies were at unclear risk for incomplete outcome data because reasons for withdrawal were not described (Andreoli 1987; Deventer 2001; Dew 1983; Green 1998; Hanauer 1996; Hawthorne 2012; Kruis 2001; Miner 1995; Pica 2012; Rijk 1992; Rutgeerts 1989; Sandberg‐Gertzen 1986; Travis 1994).
Selective reporting
All studies were at low risk of bias for selective reporting.
Other potential sources of bias
All studies appeared free from other potential sources of bias.
Effects of interventions
See: Summary of findings 1 Oral 5‐aminosalicylic acid versus placebo for maintenance of remission in ulcerative colitis; Summary of findings 2 Oral 5‐aminosalicylic acid versus sulfasalazine for maintenance of remission in ulcerative colitis; Summary of findings 3 Once‐daily dosing versus conventional dosing for maintenance of remission in ulcerative colitis; Summary of findings 4 Oral 5‐aminosalicylic acid versus comparator 5‐aminosalicylic acid formulation for maintenance of remission in ulcerative colitis
5‐Aminosalicylic acid versus placebo
Endoscopic or clinical relapse
Eight trials (1555 participants) reported treatment outcomes in terms of failure to maintain clinical or endoscopic remission (Ardizzone 1999; Gordon 2016; Hanauer 1996; Hawkey 1997; Lichtenstein 2010; Miner 1995; Sandberg‐Gertzen 1986; Wright 1993). At six to 12 months, 37% (335/907) of 5‐ASA participants relapsed compared to 52% (335/648) of placebo participants (RR 0.68, 95% CI 0.61 to 0.76; I² = 10%; high‐certainty evidence; Analysis 1.1). There was a trend towards greater efficacy with higher doses of 5‐ASA with a benefit for the 1 g/day to 1.9 g/day (RR 0.65, 95% CI 0.56 to 0.75; I² = 0%) and the 2 g/day or greater subgroups (RR 0.73, 95% CI 0.60 to 0.89; I² = 71%). The pooled RR was similar when calculated exclusively with those trials with endpoints at 12 months (RR 0.68, 95% CI 0.61 to 0.76) (Ardizzone 1999; Miner 1995; Wright 1993). Two trials involving olsalazine had a pooled RR of 0.76 (95% CI 0.58 to 0.99) (Sandberg‐Gertzen 1986; Wright 1993). Two trials involving Asacol (Ardizzone 1999; Hanauer 1996), had a pooled RR of 0.73 (95% CI 0.60 to 0.88). See summary of findings Table 1.
Adherence to medication regimen
None of the studies reported adherence to medication regimen.
Adverse events
Five studies (1132 participants) reported the proportion of participants who experienced at least one AE (Gordon 2016; Hanauer 1996; Lichtenstein 2010; Miner 1995; Wright 1993). There was no difference in the incidence of AEs between 5‐ASA and placebo participants at six to 12 months. About 44% (306/702) of 5‐ASA participants experienced at least one AE compared to 40% (172/430) of placebo participants (RR 0.93, 95% CI 0.73 to 1.18; I² = 56%; moderate‐certainty evidence; Analysis 1.2). The heterogeneity appeared to be a result of the inclusion of one specific trial (Wright 1993). Wright 1993 reported a significantly higher AE rate in the 5‐ASA group compared to placebo, mostly due to a high rate of olsalazine‐related diarrhea in the 5‐ASA group. To investigate if this study was the source of the heterogeneity, we repeated the analysis excluding this trial. The pooled analysis of the ITT population now included four studies and 1031 participants (Gordon 2016; Hanauer 1996; Lichtenstein 2010; Miner 1995). Overall, 45% (294/653) of 5‐ASA participants experienced at least one AE compared to 45% (170/378) of placebo participants (RR 0.91, 95% CI 0.79 to 1.06; I² = 12%; Analysis 1.3). Commonly reported AEs in the placebo‐controlled trials included: headache, nausea, abdominal pain, dyspepsia, bloating, influenza syndrome, rhinitis, diarrhea, and nasopharyngitis. See summary of findings Table 1.
Serious adverse events
Three studies (826 participants) reported SAEs (Gordon 2016; Hanauer 1996; Lichtenstein 2010). About 1% (6/550) of participants in the 5‐ASA group compared to 2% (5/276) of participants in the placebo group at six to 12 months had at least one SAE (RR 0.60, 95% CI 0.19 to 1.84; I² = 0%; low‐certainty evidence; Analysis 1.4). Reported SAEs included UC aggravation, acute pancreatitis, moderate ventricular dysfunction, intestinal obstruction, and esophagitis. See summary of findings Table 1.
Withdrawals due to adverse events
Seven studies (1454 participants) reported the proportion of participants withdrawn due to AEs (Ardizzone 1999; Gordon 2016; Hanauer 1996; Hawkey 1997; Lichtenstein 2010; Miner 1995; Wright 1993). There were withdrawals due to AEs for 5% (43/855) of 5‐ASA participants compared to 5% (27/599) of placebo participants at six to 12 months (RR 1.22, 95% CI 0.76 to 1.95; I² = 37%; moderate‐certainty evidence; Analysis 1.5). The heterogeneity appeared to be a result of the inclusion of one specific trial (Wright 1993). To investigate if this study was the source of the heterogeneity, we repeated the analysis excluding this trial. The pooled analysis of the ITT population now included six studies and 1353 participants (Ardizzone 1999; Gordon 2016; Hanauer 1996; Hawkey 1997; Lichtenstein 2010; Miner 1995). Overall, 4% (31/806) of 5‐ASA participants were withdrawn due to AEs compared to 5% (25/547) of placebo participants (RR 0.86, 95% CI 0.50 to 1.47; I² = 0%; Analysis 1.6). Common AEs leading to withdrawal include UC aggravation, diarrhea, headache, and paresthesia. See summary of findings Table 1.
Withdrawals after study entry
Five studies (1074 participants) reported the proportion of participants excluded or withdrawn after entry (Ardizzone 1999; Hanauer 1996; Lichtenstein 2010; Miner 1995; Wright 1993). About 19% (113/592) of 5‐ASA participants were withdrawn or excluded after entry compared to 18% (89/482) of placebo participants at six to 12 months (RR 1.13, 95% CI 0.88 to 1.44; I² = 11%; moderate‐certainty evidence; Analysis 1.7). See summary of findings Table 1.
5‐Aminosalicylic acid versus sulfasalazine
Twelve trials (1655 participants) compared the efficacy of 5‐ASA and SASP (Andreoli 1987; Ardizzone 1995; Dew 1983; Ireland 1988a; Kiilerich 1992; Kruis 1995; McIntyre 1988; Mulder 1988; Nilsson 1995; Rijk 1992; Riley 1988; Rutgeerts 1989). Eight studies limited the dose of SASP to 2 g/day; one trial to 4 g/day; one trial had a mean dose of SASP of 2.7 g/day, which ranged from 2.4 g/day to 4.4 g/day (see Characteristics of included studies). See summary of findings Table 2.
Endoscopic or clinical relapse
The outcome was defined as the failure to maintain clinical or endoscopic remission (withdrawals and relapses). About 48% (416/871) of 5‐ASA participants relapsed compared to 43% (336/784) of SASP participants at six to 18 months (RR 1.14, 95% CI 1.03 to 1.27; I² = 17%; high‐certainty evidence; Analysis 2.1).
An analysis was done limited to those studies with endpoints at 12 months (Andreoli 1987; Ardizzone 1995; Kiilerich 1992; Mulder 1988; Nilsson 1995; Rijk 1992; Riley 1988; Rutgeerts 1989), and there was no difference between the 5‐ASA and SASP groups (RR 1.10, 95% CI 0.98 to 1.23). Similarly, when the analysis was limited to studies that did not use olsalazine (Andreoli 1987; Ardizzone 1995; Dew 1983; McIntyre 1988; Mulder 1988; Riley 1988; Rutgeerts 1989), there was no difference between groups (RR 1.08, 95% CI 0.92 to 1.26; Analysis 2.2).
Three trials involving Claversal had a pooled RR of 1.15 (95% CI 0.95 to 1.40) (Andreoli 1987; Ardizzone 1995; Rutgeerts 1989). When the five trials involving olsalazine were pooled, the resulting odds ratio was 1.20 (95% CI 1.04 to 1.38), thus demonstrating that SASP was more effective than olsalazine for maintenance of remission (Ireland 1988a; Kiilerich 1992; Kruis 1995; Nilsson 1995; Rijk 1992). See summary of findings Table 2.
Adherence to medication regimen
None of the studies reported adherence to medication regimen.
Adverse events
Seven studies (1138 participants) reported the proportion of participants who experienced at least one AE (Andreoli 1987; Ireland 1988a; Kruis 1995; McIntyre 1988; Mulder 1988; Nilsson 1995; Rutgeerts 1989). About 16% (98/608) of 5‐ASA participants and 16% (84/530) of SASP participants experienced at least one AE at six to 18 months (RR 1.07, 95% CI 0.82 to 1.40; I² = 41%; moderate‐certainty evidence; Analysis 2.3). Three olsalazine trials including 634 participants that were homogeneous (I² = 0%) had a pooled odds ratio of 1.27 (95% CI 0.92 to 1.76) (Ireland 1988a; Kruis 1995; Nilsson 1995). Commonly reported AEs in the SASP trials included: headache, anorexia or appetite loss, nausea, vomiting, abdominal pain, dyspepsia, excessive flatus, bloating, urticaria and rash. Five studies involving olsalazine (Ireland 1988a; Kiilerich 1992; Kruis 1995; Nilsson 1995; Rijk 1992),and two studies involving Claversal (Andreoli 1987; Rutgeerts 1989), reported diarrhea. See summary of findings Table 2.
Serious adverse events
None of the studies reported SAEs.
Withdrawals due to adverse events
Ten studies (1585 participants) reported the proportion of participants withdrawn due to AEs (Ardizzone 1995; Ireland 1988a; Kiilerich 1992; Kruis 1995; McIntyre 1988; Mulder 1988; Nilsson 1995; Rijk 1992; Riley 1988; Rutgeerts 1989). About 7% (56/832) of 5‐ASA participants were withdrawn due to AEs compared to 5% (41/753) of SASP participants at six to 18 months (RR 1.27, 95% CI 0.87 to 1.87; I² = 0%; moderate‐certainty evidence; Analysis 2.4).
In five olsalazine trials including 906 participants, 9.2% of those receiving olsalazine and 6.2% of those receiving SASP were withdrawn because of AEs (RR 1.61, 95% CI, 1.01 to 2.56) (Ireland 1988a; Kiilerich 1992; Kruis 1995; Nilsson 1995; Rijk 1992). The results from two Claversal trials including 422 participants were not different (RR 1.10, 95% CI, 0.48 to 2.54) (Ardizzone 1995; Rutgeerts 1989). Nine studies involving 1497 participants reported the proportion of participants excluded or withdrawn after entry (excluding relapses) (Ireland 1988a; Kiilerich 1992; Kruis 1995; McIntyre 1988; Mulder 1988; Nilsson 1995; Rijk 1992; Riley 1988; Rutgeerts 1989). See summary of findings Table 2.
Withdrawals after study entry
About 19% (150/788) of 5‐ASA participants were excluded or withdrawn after entry compared to 15% (109/709) of SASP participants at six to 18 months (RR 1.30, 95% CI 1.04 to 1.63; Analysis 2.5). There was no significant heterogeneity detected (I² = 29%). Withdrawals or exclusions after entry were significantly higher in five olsalazine trials involving 906 participants (Ireland 1988a; Kiilerich 1992; Kruis 1995; Nilsson 1995; Rijk 1992). About 17% of olsalazine participants were withdrawn or excluded after entry compared to 12% of SASP participants (RR 1.51, 95% CI 1.09 to 2.08). Common AEs leading to withdrawal include diarrhea, abdominal pain, indigestion, and rash. See summary of findings Table 2.
Once‐daily dosing versus conventional dosing
Endoscopic or clinical relapse
Three trials (1871 participants) reported treatment outcomes in terms of failure to maintain clinical or endoscopic remission at six months (D'Haens 2012; Kane 2003b; Sandborn 2010). About 19% (177/939) of once‐daily participants relapsed compared to 18% (172/932) of conventional‐dosing participants (RR 1.02, 95% CI 0.85 to 1.23; I² = 0%; Analysis 3.1). None of the subgroup comparisons by formulation showed any differences in efficacy between once‐daily dosing and conventional dosing. However, only two formulations were evaluated in this pooled analysis.
Ten trials (3910 participants) reported treatment outcomes in terms of failure to maintain clinical or endoscopic remission at 12 to 13 months (Dignass 2009a; Hawthorne 2012; Kamm 2008; Kane 2008b; Kruis 2011; Park 2019; Prantera 2009; Sandborn 2010; Suzuki 2017; Watanabe 2013). About 37% (717/1939) of once‐daily participants relapsed compared to 39% (770/1971) of conventional‐dosing participants (RR 0.94, 95% CI 0.88 to 1.01; I² = 32%; high‐certainty evidence; Analysis 3.2). The subgroup comparison for Pentasa favored once‐daily dosing compared to conventional twice‐daily dosing (RR 0.75, 95% CI 0.60 to 0.93). None of the other subgroup comparisons (by formulation) showed any differences in efficacy between once‐daily dosing and conventional dosing. See summary of findings Table 3.
Adherence to medication regimen
Nine trials (2306 participants) reported adherence with study medication at study endpoint (Dignass 2009a; Hawthorne 2012; Kamm 2008; Kane 2003b; Kane 2008b; Kruis 2011; Park 2019; Prantera 2009; Watanabe 2013). Overall, 9% (106/1152) of participants in the once‐daily group failed to adhere to their medication regimen compared to 7% (84/1154) of participants in the conventional‐dosing group (RR 1.18, 95% CI 0.72 to 1.93; I² = 57%; moderate‐certainty evidence; Analysis 3.3) (6 months for Kane 2003b, 13 months for Watanabe 2013, and 12 months for the other studies in the pooled analysis). The heterogeneity appeared to be a result of the inclusion of two specific trials (Hawthorne 2012; Kamm 2008). Kamm 2008 reported a higher compliance rate of 99.6% in the twice‐daily dosing group compared to 93.3% in the once‐daily group. Hawthorne 2012 reported a higher compliance rate of 97.1% in the once‐daily dosing group compared to 85.5% in the three times‐daily dosing group. To investigate if these studies were the source of the heterogeneity, we repeated the analysis excluding these trials. The pooled analysis of the ITT population now included seven studies and 1642 participants (Dignass 2009a; Kane 2003b; Kane 2008b; Kruis 2011; Park 2019; Prantera 2009; Watanabe 2013). Overall, 11% (88/830) of participants in the once‐daily group failed to adhere to their medication regimen compared to 8% (67/812) of participants in the conventional‐dosing group (RR 1.22, 95% CI 0.92 to 1.62; I² = 0%; Analysis 3.4). See summary of findings Table 3.
Adverse events
Eight studies (3497 participants) reported the proportion of participants who experienced at least one AE (D'Haens 2012; Dignass 2009a; Kamm 2008; Kruis 2011; Park 2019; Prantera 2009; Suzuki 2017; Watanabe 2013). About 48% of once‐daily (835/1739) and 49% (862/1758) of conventional‐dosing participants experienced at least one AE at six to 13 months (RR 0.98, 95% CI 0.92 to 1.04; I² = 0%; high‐certainty evidence; Analysis 3.5). The most common AEs reported in the trials assessing once‐daily dosing included flatulence, dyspepsia, abdominal pain, nausea, diarrhea, headache, nasopharyngitis, inflammation of the upper respiratory tract, gastroenteritis, dental caries, and worsening of UC. See summary of findings Table 3.
Serious adverse events
Seven studies (3196 participants) reported the proportion of participants who experienced at least one SAE (D'Haens 2012; Dignass 2009a; Kamm 2008; Kruis 2011; Park 2019; Prantera 2009; Suzuki 2017). About 3% (41/1587) of participants in the once‐daily group experienced at least one SAE compared to 2% (35/1609) of participants in the conventional‐dosing group at six to 13 months (RR 1.20, 95% CI 0.77 to 1.87; I² = 0%; moderate‐certainty evidence; Analysis 3.6). Reported SAEs included UC aggravation, acute pancreatitis, anal fistula, pneumonia, melena, nephrolithiasis, and hypersensitivity pneumonitis. See summary of findings Table 3.
Withdrawals due to adverse events
Eight studies (4340 participants) reported the proportion of participants who were withdrawn due to AEs (D'Haens 2012; Dignass 2009a; Kamm 2008; Kruis 2011; Prantera 2009; Sandborn 2010; Suzuki 2017; Watanabe 2013). Withdrawals due to AEs were 2% (36/2160) in the once‐daily group compared to 1% (31/2180) in the conventional‐dosing group at six to 13 months (RR 1.18, 95% CI 0.74 to 1.89; I² = 15%; very low‐certainty evidence; Analysis 3.7). See summary of findings Table 3.
Withdrawals after study entry
Seven studies (3737 participants) reported the proportion of participants who were excluded or withdrawn after entry (D'Haens 2012; Dignass 2009a; Kamm 2008; Kruis 2011; Prantera 2009; Sandborn 2010; Watanabe 2013). Approximately 15% (276/1858) of once‐daily and 15% of conventional‐dosing (281/1879) participants were excluded or withdrawn after entry at six to 13 months (RR 0.99, 95% CI 0.85 to 1.15; I² = 0%; high‐certainty evidence; Analysis 3.8). Common AEs leading to withdrawal include UC aggravation, flatulence, nausea, and abdominal distension. See summary of findings Table 3.
5‐Aminosalicylic acid versus comparator 5‐aminosalicylic acid formulation
Endoscopic or clinical relapse
Six studies (707 participants) reported treatment outcomes in terms of the failure to maintain clinical or endoscopic remission at six to 18 months (Courtney 1992; Deventer 2001; Green 1998; Ito 2010; Kruis 2001; Mahmud 2002). The overall pooled RR showed no difference in relapse between various formulations of 5‐ASA (including balsalazide, Pentasa, and olsalazine) and comparator formulations of 5‐ASA (including Asacol and Salofalk). About 44% (158/358) of participants in the 5‐ASA group relapsed compared to 41% (142/349) of participants in the 5‐ASA comparator group. The pooled RR of relapse was 1.08 using a fixed‐effect model (95% CI 0.91 to 1.28; I² = 31%; Analysis 4.1). The GRADE analysis indicated that the overall certainty of the evidence for the primary outcome (failure to maintain clinical or endoscopic remission) was low due to sparse data (300 events) and a high risk of bias (lack of blinding) in two studies in the pooled analysis. See summary of findings Table 4.
Adherence to medication regimen
None of the studies reported adherence to medication regimen.
Adverse events
Four studies (357 participants) reported the proportion of participants who experienced at least one AE between various formulations of 5‐ASA (including balsalazide, Pentasa, and olsalazine) and comparator formulations of 5‐ASA (including Asaco and Salofalk) (Green 1998; Ito 2010; Kruis 2001; Mahmud 2002). About 64% (116/182) of participants in the 5‐ASA group experienced at least one AE compared to 69% (120/175) of participants in the 5‐ASA comparator group at six to 12 months (RR 0.94, 95% CI 0.83 to 1.07; I² = 8%; low‐certainty evidence; Analysis 4.2). The most common AEs reported in these trials included dyspepsia, abdominal pain, nausea, distension, diarrhea, headache, nasopharyngitis or respiratory infections, influenza‐like disorder, and rash. See summary of findings Table 4.
Serious adverse events
One study (95 participants) reported on the proportion of participants who experienced at least one SAE (Green 1998). About 6% (3/49) of participants in the 5‐ASA group experienced at least one SAE compared to 11% (5/46) of participants in the 5‐ASA comparator group (RR 0.56, 95% CI 0.14 to 2.22; Analysis 4.3). Commonly reported SAEs included a urinary tract infection, a severe complication of UC, cardiac arrest, ischemic heart disease, fracture of the scaphoid, and a spigelian hernia. See summary of findings Table 4.
Withdrawals due to adverse events
Five studies (457 participants) reported the proportion of participants who were withdrawn due to AEs (Courtney 1992; Green 1998; Ito 2010; Kruis 2001; Mahmud 2002). About 6% (13/232) of participants in the 5‐ASA group were withdrawn due to AEs compared to 4% (10/225) of participants in the 5‐ASA comparator group at 12 months (RR 1.25, 95% CI 0.56 to 2.78; I² = 0%; very low‐certainty evidence; Analysis 4.4). Common AEs leading to withdrawal include headache, lethargy, hypertension, malaise, and abdominal pain. See summary of findings Table 4.
Withdrawals after study entry
Five studies (457 participants) reported the proportion of participants who were excluded or withdrawn after entry between various formulations of 5‐ASA (including balsalazide, Pentasa, and olsalazine) and comparator formulations of 5‐ASA (including Asacol and Salofalk) (Courtney 1992; Green 1998; Ito 2010; Kruis 2001; Mahmud 2002). About 28% (64/232) of participants in the 5‐ASA group were excluded or withdrawn after entry compared to 22% (50/225) of participants in the 5‐ASA comparator group at six to 12 months (RR 1.23, 95% CI 0.90 to 1.70; I² = 0%; moderate‐certainty evidence; Analysis 4.5). See summary of findings Table 4.
5‐Aminosalicylic acid dose ranging
Several randomized trials looked at dose‐ranging for various formulations of 5‐ASA including Asacol, balsalazide, olsalazine, Salofalk, and Pentasa.
Endoscopic or clinical relapse
Four studies examined the efficacy of various doses of Asacol for maintenance of clinical or endoscopic remission (Deventer 2001; Hanauer 1996; Paoluzi 2005; Pica 2012). Pica 2012 found no difference in efficacy between Asacol 4.8 g/day compared to 2.4 g/day. About 29% (16/56) of participants in the Asacol 4.8 g/day group relapsed compared to 36% (20/56) in the 2.4 g/day group (RR 0.80, 95% CI 0.46 to 1.38; 112 participants; very low‐certainty evidence; Analysis 5.1). Deventer 2001 found no difference in efficacy between Asacol 3.2 g/day compared to 2 g/day. About 51% (70/138) of participants in the Asacol 3.2 g/day group relapsed compared to 48% (59/124) of participants in the 2 g/day group (RR 1.07, 95% CI 0.83 to 1.37; 262 participants; Analysis 5.1). Paoluzi 2005 found no difference in efficacy between Asacol 2.4 g/day compared to 1.2 g/day. About 70% (56/80) of participants in the Asacol 2.4 g/day group relapsed compared to 74% (56/76) in the 1.2 g/day group (RR 0.95, 95% CI 0.78 to 1.16; 156 participants; Analysis 5.1). Hanauer 1996 found no difference in efficacy between Asacol 1.6 g/day compared to 0.8 g/day. About 56% (49/87) of participants relapsed in the 1.6 g/day group compared to 56% (50/90) of participants in the 0.8 g/day group (RR 1.01, 95% CI 0.78 to 1.32; 177 participants; Analysis 5.1).
Three studies examined the efficacy of various doses of balsalazide (3 g/day to 6 g/day) for maintenance of clinical or endoscopic remission (Giaffer 1992a; Green 1992; Kruis 2001). Two of these studies compared balsalazide 6 g/day to 3 g/day (Green 1992; Kruis 2001). About 23% (24/104) of participants in the 6 g/day group relapsed compared to 33% (37/112) of participants in the 3 g/day group (RR 0.76, 95% CI 0.21 to 2.79; 216 participants). However, these results should be interpreted with caution as there was significant heterogeneity (I² = 86%). Giaffer 1992a compared balsalazide 4 g/day to 2 g/day and found a difference favoring the 4 g/day dose group. About 37% (25/68) of participants in the 4 g/day group relapsed compared to 55% (36/65) of participants in the 2 g/day group (RR 0.66, 95% CI 0.45 to 0.97; 133 participants; Analysis 5.1).
Travis 1994 found no significant difference in efficacy between olsalazine 2 g/day and 1 g/day. About 40% of participants in both dose groups relapsed (RR 1.01, 95% CI 0.66 to 1.54; 127 participants; Analysis 5.1). Kruis 2011 found a difference between Salofalk granules 3 g/day and 1.5 g/day. About 25% (55/217) of participants in the Salofalk 3 g/day group relapsed compared to 39% (83/212) of participants in the 1.5 g/day group (RR 0.65, 95% CI 0.49 to 0.86; 429 participants; Analysis 5.1). Fockens 1995 found no significant difference in efficacy between Pentasa 3.0 g/day and 1.5 g/day. About 28% (23/82) of participants in the 3.0 g/day group relapsed compared to 38% (33/87) in the 1.5 g/day group (RR 0.74, 95% CI 0.48 to 1.15; 169 participants; Analysis 5.1).
Adherence to medication regimen
None of the studies reported adherence to medication regimen.
Adverse events
Five dose‐ranging studies (977 participants) reported the proportion of participants who experienced at least one AE at six to 12 months (Hanauer 1996; Kruis 2001; Kruis 2011; Paoluzi 2005; Travis 1994). Kruis 2011 found a difference in the proportion of participants who experienced at least one AE between Salofalk 3 g/day and 1.5 g/day both dosed once daily. About 41% (89/217) of participants in the 3 g/day group experienced at least one AE compared to 55% (117/212) of participants in the 1.5 g/day group (RR 0.74, 95% CI 0.61 to 0.91; 429 participants; Analysis 5.2). Hanauer 1996 found a difference in the proportion of participants who experienced at least one AE between Asacol 1.6 g/day and 0.8 g/day. About 41% (36/87) of participants in the Asacol 1.6 g/day group experienced at least one AE compared to 22% (20/90) of participants in the 0.8 g/day group (RR 1.86; 95% CI 1.18 to 2.95; 177 participants; Analysis 5.2). There were no differences in the incidence of AEs between Asacol 2.4 g/day and 1.2 g/day (RR 2.85, 95% CI 0.12 to 68.95; 156 participants), balsalazide 6.0 g/day and 3.0 g/day (RR 1.40, 95% CI 0.88 to 2.24; 88 participants; Analysis 5.2), and olsalazine 2.0 g/day and 1.0 g/day (RR 1.37, 95% CI 0.94 to 1.99; 127 participants; Analysis 5.2). Common AEs include headaches, abdominal pain, and diarrhea.
Serious adverse events
Two studies (606 participants) reported on the incidence of SAEs between the high‐dose and low‐dose groups (Hanauer 1996; Kruis 2001). About 3% (9/304) of participants in the high‐dose group compared to 3% (8/302) of participants in the low‐dose 5‐ASA group experienced an SAE at six 12 months (RR 1.11, 95% CI 0.43 to 2.82; low‐certainty evidence; Analysis 5.3). The trials did not report the specific SAEs.
Withdrawals due to adverse events
Seven dose‐ranging studies (1260 participants) reported the proportion of participants who were withdrawn due to AEs at six to 12 months (Fockens 1995; Giaffer 1992a; Green 1992; Hanauer 1996; Kruis 2001; Kruis 2011; Paoluzi 2005). There were no differences in withdrawal due to AEs between Asacol 2.4 g/day and 1.2 g/day (RR 2.85, 95% CI 0.12 to 68.95; 1 study, 156 participants; Analysis 5.4); Asacol 1.6 g/day and 0.8 g/day (RR 0.34, 95% CI 0.04 to 3.25; 1 study, 177 participants; Analysis 5.4); balsalazide 6.0 g/day and 3.0 g/day (RR 0.59, 95% CI 0.21 to 1.70; 2 studies, 196 participants; Analysis 5.4); balsalazide 4.0 g/day and 2.0 g/day (RR 1.43, 95% CI 0.54 to 3.80; 1 study, 133 participants; Analysis 5.4); and Pentasa 3.0 g/day and 1.5 g/day (RR 1.06, 95% CI 0.07 to 16.69; 1 study, 169 participants; Analysis 5.4). Common AEs leading to withdrawal included headache, hypertension, malaise, and abdominal pain.
Withdrawals after study entry
Eight dose‐ranging studies (1387 participants) reported the proportion of participants who were excluded or withdraw after entry at six to 12 months (Fockens 1995; Giaffer 1992a; Green 1992; Hanauer 1996; Kruis 2001; Kruis 2011; Paoluzi 2005; Travis 1994). There was a difference between balsalazide 6.0 g/day and 3.0 g/day (RR 0.47, 95% CI 0.26 to 0.84; 2 studies, 196 participants; Analysis 5.5) and between Salofalk 3 g/day and 1.5 g/day (RR 0.66, 95% CI 0.46 to 0.93; 1 study, 429 participants; Analysis 5.5). There were no significant differences in exclusions or withdrawals after entry between Asacol 2.4 g/day and 1.2 g/day (RR 0.95, 95% CI 0.38 to 2.40; 1 study, 156 participants; Analysis 5.5); Asacol 1.6 g/day and 0.8 g/day (RR 1.23, 95% CI 0.80 to 1.90; 1 study, 177 participants; Analysis 5.5); balsalazide 4.0 g/day and 2.0 g/day (RR 1.27, 95% CI 0.77 to 2.12; 1 study, 133 participants; Analysis 5.5); olsalazine 2.0 g/day and 1.0 g/day (RR 1.75, 95% CI 0.83 to 3.70; 1 study, 127 participants; Analysis 5.5); and Pentasa 3.0 g/day and 1.5 g/day (RR 0.83, 95% CI 0.44 to 1.55; 1 study, 169 participants; Analysis 5.5).
Discussion
Summary of main results
This updated systematic review largely confirms the results of previous meta‐analyses (Feagan 2012; Sutherland 1993; Sutherland 1997; Sutherland 2006; Wang 2016). This updated review includes 44 studies and 9967 participants which greatly increases statistical power. The results of this systematic review provide strong evidence that point towards a number of conclusions.
The effectiveness of oral 5‐ASA preparations for maintenance of remission in quiescent UC was confirmed. Oral 5‐ASA is superior to placebo for maintenance of remission in UC. There may be a trend towards greater efficacy with higher doses of 5‐ASA with a benefit for the 1 g/day to 1.9 g/day and the 2 g/day or greater dosage groups.
An interesting result was that SASP had a modest benefit over 5‐ASA. When the pooled analysis was limited to trials with endpoints at 12 months, the difference was no longer significant. Nevertheless, certain limitations may have resulted from having combined all trials regardless of whether relapse was defined in terms of clinical or endoscopic criteria. It is possible that the 'superiority' of SASP over 5‐ASA reflects the ITT analysis that was employed. This technique considers all participants who received the medication and penalizes medications with high dropout rates (e.g. olsalazine). A per protocol analysis, which includes those participants who are compliant and who tolerate the medication, might not support a 'superiority' claim.
When data for maintenance therapy were subgrouped according to the specific 5‐ASA preparation, olsalazine was significantly inferior to SASP. Firm conclusions regarding other preparations, which have generally been subject to less‐rigorous clinical evaluation, could not be surmised. In the case of olsalazine, it appeared that the reduced efficacy was influenced by the significantly higher proportions of withdrawals due to AEs and total exclusions or withdrawals of participants receiving olsalazine compared to those receiving SASP. In fact, if the analysis of efficacy was restricted to relapses as treatment failures, excluding withdrawals for other reasons, there was no significant difference between olsalazine and SASP (data not shown). The difference may also be related to a misclassification bias in which participants who developed diarrhea were falsely classified as treatment relapses rather than having experienced AEs.
The overall superiority of SASP over 5‐ASA for maintenance therapy may also be attributable to certain pharmacological properties of SASP, including potential therapeutic effects of the sulfapyridine moiety, that are not observed with other 5‐ASA delivery systems. The mechanisms of action of SASP and its metabolites have been reviewed by Greenfield 1993.
It was apparent that the newer 5‐ASA preparations had adverse effects in several participants. However, the incidence of AEs, SAEs, and withdrawals due to the 5‐ASA formulations did not significantly differ from that associated with placebo. There was also no apparent difference between the number of AEs caused by SASP and 5‐ASA. It should be noted that there may have been a bias in favor of SASP since many of the studies involved participants who were known to have tolerated SASP in the past. This may have minimized SASP‐related AEs in these trials.
In contrast to these results, olsalazine was associated with a significantly higher proportion of withdrawals due to AEs relative to SASP. The most common AE attributed to olsalazine was diarrhea, an effect previously observed in approximately 10% of participants receiving the drug (Ireland 1988b). It has been suggested that protocol alterations may reduce withdrawal rates in future trials since it has been reported that encouraging participants to take olsalazine with meals appears to reduce the incidence of diarrhea to approximately 3% of participants (Jarnerot 1996). However, four of the five olsalazine‐SASP trials reported that such recommendations were in fact made (Kiilerich 1992; Kruis 1995; Nilsson 1995; Rijk 1992).
High‐certainty evidence suggests that 5‐ASA administered once daily is as effective as conventional dosing (twice or three times daily) for maintenance of remission over six‐ and 12‐month periods in participants with quiescent UC. With the exception of Pentasa, subgroup analyses by drug formulation showed no significant differences in efficacy between once‐daily and conventional dosing for maintenance of remission. Dignass 2009a found that 2 g of Pentasa dosed once daily was superior to 1 g Pentasa dosed twice daily for maintenance of remission at 12 months. The other Pentasa study found no difference between once‐daily and conventional dosing for maintenance of remission. A plausible biological explanation for the Dignass 2009a finding is not readily apparent to us.
The results of this meta‐analysis suggest that there is no difference in safety between once‐daily and conventional‐dose 5‐ASA. There were no differences between once‐daily and conventional‐dose 5‐ASA for safety outcomes including the overall incidence of AEs, SAEs, or withdrawal from treatment due to an AE. In keeping with the well‐established safety profile of 5‐ASA, most of the AEs reported in the studies assessing once‐daily dosing were mild to moderate in intensity. Common AEs included gastrointestinal symptoms (e.g. flatulence, abdominal pain, nausea, and diarrhea), headache, and worsening UC.
Important patient preference and adherence differences may exist between dosing regimens. In the study that measured participant preference, most participants preferred once‐daily dosing to conventional dosing (Sandborn 2010). Although it is generally believed that administration of fewer pills and less‐frequent dosing improves both efficacy and adherence, we could not demonstrate the superiority of once‐daily dosing for either of these outcomes. This result suggests that patient adherence may not be enhanced by once‐daily dosing in the clinical trial setting. Several possible explanations exist for these observations, however the most plausible one concerns the unique aspects of the clinical trial environment. It is noteworthy that adherence with medication was remarkably high in the studies that measured this outcome (Dignass 2009a; Hawthorne 2012; Kamm 2008; Kruis 2011; Prantera 2009). The pooled adherence rate for the maintenance of remission studies was 86% for the once‐daily dosing group compared to 89% for the conventional‐dosing group. These rates likely reflect the highly supervised environment in which the studies were conducted. Adherence with medication in clinical trials is generally greater than in clinical practice since participants are highly selected volunteers who are more likely, in general, to be adherent with drug regimens (Andrade 1995; Kane 2001; Kane 2006; Kane 2008a). In addition, adherence is continuously reinforced during the clinical trial process. Thus, it may be difficult to detect differences in adherence between once‐daily and multiple‐dose regimens in this setting.
Accordingly, a need exists to compare dosing regimens in large‐scale community‐based studies. In this regard, reported adherence rates in community‐based studies range from 40% to 60% and are especially poor among patients in remission (Kane 2001; Kane 2003a; Levy 1999; Shale 2003). However, whether once‐daily dosing regimens improve adherence in the community remains unknown. Although Kane 2003b demonstrated significantly higher adherence among people receiving once‐daily dosing compared to conventional dosing at three months, there were no significant differences at six months. This time‐dependent effect has been observed in a larger study (Sandborn 2010). Sandborn 2010 found significantly higher adherence among participants using once‐daily dosing compared to conventional dosing at three months. However, there was no significant difference in adherence at six and 12 months (Sandborn 2010).
Experience from other indications suggest that factors other than the dosing regimen are important for long‐term compliance (Brixner 2007; Kane 2008a). Long‐term observations in people with UC as well as in other conditions indicate that patients' and physicians' behaviors play a dominant role in adherence (Beaulieu 2009; Magowan 2006). The patient–physician relationship should reinforce adherence through education, open communication, and mutual agreement regarding the value of treatment (Kane 2008a). To ensure continued adherence in a community‐based setting, Sandborn 2010 have emphasized the importance of healthcare providers evaluating and reinforcing compliance with patients after three months of maintenance therapy.
There may be little or no difference in efficacy between the various formulations of oral 5‐ASA. The overall pooled RR (6 studies, 707 participants) showed no difference in relapse between various formulations of 5‐ASA (including balsalazide, Pentasa, and olsalazine) and comparator formulations of 5‐ASA (including Asacol and Salofalk). However, a GRADE analysis indicated that the overall certainty of the evidence for the primary outcome (failure to maintain clinical or endoscopic remission at 12 months) was low due to a high risk of bias (single blind and open‐label) in three studies in the pooled analysis and sparse data (see summary of findings Table 4). However, the open‐label study (Mahmud 2002), and one of the single‐blind studies (Courtney 1992), included endoscopy as an endpoint, which may provide some protection against performance and detection bias.
Pharmacokinetic studies suggest that systemic exposure to 5‐ASA is similar for all oral 5‐ASA formulations and 5‐ASA prodrugs (Sandborn 2002a; Sandborn 2002b; Sandborn 2002c; Sandborn 2003). The excretory function of the kidneys (as measured by the glomerular filtration rate) does not change during maintenance therapy with oral 5‐ASA or olsalazine, and nephrotoxicity is rare for Pentasa or Asacol, suggesting that the systemic exposure to 5‐ASA that occurs for doses used in clinical practice is safe for all drugs in this class (Sandborn 2002a). With the exception of olsalazine‐related diarrhea, there appears to be no difference in safety between the various formulations of oral 5‐ASA. The overall pooled RRs showed no differences in the incidence of AEs, SAEs, withdrawal due to AEs, or exclusions or withdrawals after entry. These results suggest that there may be little or no difference in safety across oral 5‐ASA formulations. Treatment with SASP and olsalazine may not be preferable due to the high frequency of AEs. When deciding which 5‐ASA formulations to use, physicians and patients should consider dose‐response data, adherence issues related to dose forms (size of dose form and total number of pills or capsules per day), and price (Sandborn 2002a).
Few dose‐ranging maintenance studies were performed, which limits the conclusions that can be drawn. Hanauer 1996 compared Asacol at a dosage of 1.6 g/day to 0.8 g/day and found no difference in relapse rates between groups. Deventer 2001 compared 3.2 g/day to 2 g/day and found no difference in relapse rates between groups. Paoluzi 2005 compared Asacol at a dosage of 2.4 g/day to 1.2 g/day and found no difference in relapse rates between groups. However, participants in the higher‐dosage group remained in remission longer, compared to participants in the low‐dose group. Paoluzi 2005 recommended a dosage of 2.4 g/day due to the significantly longer time to relapse in the higher‐dosage group. Pica 2012 compared 4.8 g/day to 2.4 g/day and found no difference in relapse rates between groups. Further research may be needed to determine the ideal dosage of Asacol for maintenance therapy.
Three studies compared the efficacy of high‐dose balsalazide (4.0 g/day to 6.0 g/day) to low dose balsalazide (2.0 g/day to 3.0 g/day). Giaffer 1992a found balsalazide 4.0 g/day to be significantly superior to 2.0 g/day for preventing relapses over 12 months. There were no differences in safety between groups noted. A pooled analysis of two studies comparing balsalazide 6.0 g/day to 3.0 g/day found no significant difference in relapse rates. However, these results should be interpreted with caution due to a high degree of heterogeneity and sparse data. The high degree of heterogeneity was due to the two studies having conflicting results. Green 1992 found no differences in relapse rates between the 6.0 g/day and 3.0 g/day groups at either six or 12 months. Green 1992 noted no differences in safety. Kruis 2001 found 6.0 g/day to be superior to 3 g/day for preventing relapse over 26 weeks with no differences in safety. Differences in patient populations may explain these findings. Green 1992 included participants with a very distal extent of UC and a large proportion of participants had long‐term remission at entry (e.g. greater than one year). Kruis 2001 suggested that people with more extensive UC or with frequent relapses may benefit from a higher dose of maintenance therapy.
Kruis 2011 investigated different doses of once‐daily Salofalk (3 g or 1.5 g) and found that significantly fewer participants relapsed at 12 months in the group receiving 3 g once‐daily (25%) group compared to participants in the 1.5 g group (39%). This analysis involved 439 participants and provided moderate‐certainty evidence (based on GRADE analysis) that 3 g Salofalk once daily is superior to 1.5 g Salofalk once daily for maintenance treatment of UC. There were no differences in safety between groups. In a post hoc analysis, Kruis 2011 observed that participants with active inflammation at baseline in the 3 g group continued to maintain a higher rate of remission than participants receiving lower doses (i.e. 1.5 g once daily or 0.5 g three times daily). Kruis 2011 concluded that 3 g once daily is an appropriate dose for maintenance of remission, and may be beneficial for people with signs of inflammation or in whom endoscopic data are not available. No other maintenance studies looked at dose‐ranging for once‐daily treatment using other 5‐ASA formulations.
Travis 1994 compared the efficacy of olsalazine 2.0 g/day to 1.0 g/day and 0.5 g/day. There was no significant difference in relapse at 12 months between the 2.0 g/day and 1.0 g/day groups. A dosage of 2.0 g/day was significantly superior to 0.5 g/day for preventing relapse. There were no differences in safety noted. Subgroup analysis showed that participants with proctitis and recent relapse may benefit from a dosage of 2.0 g/day (Travis 1994). Fockens 1995 compared the efficacy of Pentasa 3.0 g/day to 1.5 g/day. Although there was a trend favoring the higher dose, there was no significant difference in prevention of relapse over one year. The higher dosage was not associated with a higher incidence of AEs (Fockens 1995).
Overall completeness and applicability of evidence
Evidence presented in this review is applicable to most patients with mild‐to‐moderate UC. The review examined 5‐ASA compared to placebo, SASP, and comparator 5‐ASA. The review also examined 5‐ASA dose‐ranging studies and once‐daily compared to conventional‐dosing studies. All the efficacy and safety outcomes we aimed to report on were included in the studies. The review found the efficacy outcomes for 5‐ASA versus placebo, 5‐ASA versus SASP, and once‐daily versus conventional dosing to be of moderate‐ to high‐certainty evidence. Therefore, this implies this area does not need additional studies. However, the evidence regarding the safety outcomes for most comparisons ranged from very low to moderate. In addition, the efficacy outcomes for the oral 5‐ASA versus comparator 5‐ASA and high‐dose versus low‐dose oral 5‐ASA ranged from low to moderate. Therefore, additional studies assessing these efficacy and safety outcomes may change the overall results.
Quality of the evidence
Fourteen studies were at low risk and 30 studies were at unclear risk for randomization because the methods of randomization were not described. Twenty‐five studies were at low risk and 19 studies were at unclear risk for allocation concealment because the methods were not adequately described. Thirty‐two studies were double blind and at low risk of bias. One study was at unclear risk because the placebo capsules were not described in detail and 10 studies were at high risk of bias because they were either single blind or open label. Thirty‐one studies were at low risk of bias and thirteen studies were at unclear risk for incomplete outcome data because the number of dropouts or reasons for withdrawal (or both) were not provided.
For the oral 5‐ASA versus placebo comparison, the certainty of the evidence for the outcome failure to maintain clinical or endoscopic remission was high. The certainty of the evidence for the outcomes AEs, withdrawal due to AEs, and exclusion/withdrawal after entry was moderate due to sparse data, and SAEs was low due to very sparse data (summary of findings Table 1). For the studies comparing 5‐ASA with SASP, the certainty of the evidence for the outcome failure to maintain clinical or endoscopic remission was high. The certainty of the evidence for AEs, withdrawal due to AEs, and exclusion/withdrawal after entry was moderate due to sparse data (summary of findings Table 2). For the studies comparing once‐daily dosing to conventional dosing for maintenance of remission in UC, the certainty of the evidence for failure to maintain clinical or endoscopic remission, AEs, and exclusion/withdrawal after entry was high. The certainty of the evidence for SAEs and failure to adhere to study medication outcomes was moderate due to sparse data, and lastly, withdrawal due to AEs was low due to sparse data and risk of bias (summary of findings Table 3). For the studies comparing different oral 5‐ASA formulations the certainty of the evidence for exclusion/withdrawal after entry was moderate due to sparse data. Failure to maintain clinical or endoscopic remission, AEs, and SAEs were rated as low‐certainty evidence due to sparse data and risk of bias. Withdrawal due to AEs was very low‐certainty evidence due to very sparse data and risk of bias (summary of findings Table 4).
Potential biases in the review process
The methods and reporting of this review were based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We conducted a comprehensive literature search and two review authors independently screened the studies, extracted the data, assessed the risk of bias, and performed a GRADE analysis to minimize the bias. Despite these standardized processes, there are some potential limitations to making general conclusions from this review. Almost every study utilized a unique clinical or endoscopic index. Unlike Crohn's disease, the lack of standard indices in UC prevented the collection of consistent treatment efficacy data and makes comparisons across clinical studies difficult. In addition, results were periodically obscured in several studies that failed to specify the treatment arm to which certain excluded participants were initially randomized.
Agreements and disagreements with other studies or reviews
We identified two other systematic reviews that assessed the use of 5‐ASA for maintenance of remission in UC (Ford 2011a; Ford 2011b).
Ford 2011a is a systematic review and meta‐analysis assessing the efficacy of 5‐ASA in people with UC. The review identified 11 trials of 5‐ASAs compared to placebo in people with quiescent UC. The review concluded 5‐ASA was highly effective for preventing relapse in UC and there was no difference between the types of 5‐ASA therapy (SASP, olsalazine) used for preventing relapse in UC. The review also suggested that 5‐ASA doses of 2.0 g/day or greater have greater efficacy in comparison to the other doses. The results of our current Cochrane Review agree with the Ford review. We also found that the 5‐ASA group had lower relapse rates compared to the placebo group.
Ford 2011b is a systematic review and meta‐analysis that studied once‐daily dosing compared to conventional dosing for people with quiescent UC taking 5‐ASAs. The results showed that the relapse rates, non‐compliance, and AEs did not differ between the once‐daily and conventional dosing schedules. The study concluded that once‐daily dosing is as effective as conventional dosing for the prevention of relapse in people with UC. The results of this current Cochrane Review also concluded there are no differences in the relapse, non‐compliance/adherence, and AE rates between the once‐daily and conventional dosing groups. Therefore, the results of both reviews agree with each other.
Study flow diagram.
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 1: Failure to maintain clinical or endoscopic remission at 6–12 months
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 2: Development of any adverse event at 6–12 months
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 3: Development of any adverse event (sensitivity analysis) at 6–12 months
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 4: Development of any serious adverse event at 6–12 months
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 5: Withdrawal from study due to adverse event at 6–12 months
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 6: Withdrawal from study due to adverse event (sensitivity analysis) at 6–12 months
Comparison 1: 5‐Aminosalicylic acid (5‐ASA) versus placebo, Outcome 7: Exclusion/withdrawal after entry (not due to relapse) at 6–12 months
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 1: Failure to maintain clinical or endoscopic remission at 6–18 months
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 2: Failure to maintain remission (trials without olsalazine) at 6–12 months
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 3: Development of any adverse event at 6–18 months
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 4: Withdrawal from study due to adverse event at 6–18 months
Comparison 2: 5‐Aminosalicylic acid (5‐ASA) versus sulfasalazine (SASP), Outcome 5: Exclusion/withdrawal after entry (not due to relapse) at 6–18 months
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 1: Failure to maintain clinical or endoscopic remission at 6 months](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.01.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 1: Failure to maintain clinical or endoscopic remission at 6 months
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 2: Failure to maintain clinical or endoscopic remission at 12–13 months](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.02.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 2: Failure to maintain clinical or endoscopic remission at 12–13 months
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 3: Failure to adhere to study medication regimen at study endpoint at 6–13 months](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.03.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 3: Failure to adhere to study medication regimen at study endpoint at 6–13 months
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 4: Failure to adhere to study medication regimen at 6–13 months (sensitivity analysis – excluding outliers)](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.04.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 4: Failure to adhere to study medication regimen at 6–13 months (sensitivity analysis – excluding outliers)
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 5: Development of any adverse event at 6–13 months](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.05.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 5: Development of any adverse event at 6–13 months
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 6: Development of serious adverse events at 6–13 months](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.06.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 6: Development of serious adverse events at 6–13 months
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 7: Withdrawal due to adverse event at 6–13 months](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.07.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 7: Withdrawal due to adverse event at 6–13 months
![Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 8: Exclusion/withdrawal after entry (not due to relapse) at 6–13 months](/es/cdsr/doi/10.1002/14651858.CD000544.pub5/media/CDSR/CD000544/image_n/nCD000544-CMP-003.08.svg)
Comparison 3: Once‐daily (OD) versus conventional dosing (twice [BID] or three times daily [TID]), Outcome 8: Exclusion/withdrawal after entry (not due to relapse) at 6–13 months
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 1: Failure to maintain clinical or endoscopic remission at 6–18 months
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 2: Development of any adverse event at 6–12 months
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 3: Development of any serious adverse event at 12 months
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 4: Withdrawal from study due to adverse event at 6–12 months
Comparison 4: 5‐Aminosalicylic acid (5‐ASA) versus comparator 5‐ASA, Outcome 5: Exclusion/withdrawal after entry (not due to relapse) at 6–12 months
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 1: Failure to maintain clinical or endoscopic remission at 6–18 months
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 2: Development of any adverse event at 6–12 months
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 3: Development of any serious adverse event at 6–12 months
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 4: Withdrawal from study due to adverse event at 6–12 months
Comparison 5: 5‐Aminosalicylic acid (5‐ASA) (dose ranging), Outcome 5: Exclusion/withdrawal after entry (not due to relapse) at 6–12 months
| Oral 5‐ASA vs placebo for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent UC | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 6–12 months | 584 per 1000 | 373 per 1000 | RR 0.68 | 1555 | ⊕⊕⊕⊕ | Clinical remission defined using the revised SDAI (rectal bleeding = 0, mucosal appearance ≤ 2). |
| Failure to adhere to study medication | Outcome not reported. | Not reported. | ||||
| Adverse events Follow‐up: 6–12 months | 400 per 1000 | 372 per 1000 | RR 0.93 | 1132 | ⊕⊕⊕⊝ | Common adverse events included headache, nausea, abdominal pain, dyspepsia, bloating, influenza syndrome, rhinitis, diarrhea, and nasopharyngitis. |
| Serious adverse events Follow‐up: 6–12 months | 18 per 1000 | 11 per 1000 (3 to 33) | RR 0.60 (0.19 to 1.84) | 826 (3 studies) | ⊕⊕⊝⊝ | Serious adverse events included UC aggravation, acute pancreatitis, moderate ventricular dysfunction, intestinal obstruction, and esophagitis. |
| Withdrawal due to adverse event Follow‐up: 6–12 months | 45 per 1000 | 55 per 1000 | RR 1.22 | 1454 | ⊕⊕⊕⊝ | Common adverse events leading to withdrawal included UC aggravation diarrhea, headache, and paresthesia. |
| Exclusion/withdrawal after entry Follow‐up: 6–12 months | 185 per 1000 | 209 per 1000 (162 to 266) | RR 1.13 (0.88 to 1.44) | 1074 (5 studies) | ⊕⊕⊕⊝ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; RR: risk ratio; SDAI: Sutherland Disease Activity Index; UC: ulcerative colitis. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to serious imprecision (478 events). | ||||||
| Oral 5‐ASA vs SASP for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| SASP | Oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 6–18 months | 429 per 1000 | 489 per 1000 | RR 1.14 | 1655 | ⊕⊕⊕⊕ | Clinical or endoscopic remission defined as the absence of colitis symptoms together with an absence of inflammation on sigmoidoscopy. |
| Failure to adhere to study medication | Outcome not reported. | Not reported. | ||||
| Adverse event Follow‐up: 6–18 months | 158 per 1000 | 170 per 1000 | RR 1.07 | 1138 | ⊕⊕⊕⊝ | Commonly reported adverse events in the SASP‐controlled trials included: headache, anorexia or appetite loss, nausea, vomiting, abdominal pain, dyspepsia, excessive flatus, bloating, urticaria, and rash. |
| Serious adverse events | Outcome not reported. | Not reported. | ||||
| Withdrawal due to adverse event Follow‐up: 6–18 months | 54 per 1000 | 69 per 1000 | RR 1.27 | 1585 | ⊕⊕⊕⊝ | Common adverse events leading to withdrawal included diarrhea, abdominal pain, indigestion, and rash. |
| Exclusion/withdrawal after entry Follow‐up: 6–18 months | 154 per 1000 | 200 per 1000 (160 to 251) | RR 1.30 (1.04 to 1.63) | 1497 (9 studies) | ⊕⊕⊕⊝ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; RR: risk ratio; SASP: sulfasalazine. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to imprecision (182 events). | ||||||
| Once‐daily dosing vs conventional dosing for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent UC | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Conventionally dosed oral 5‐ASA | OD oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 12–13 months | 391 per 1000 | 367 per 1000 | RR 0.94 | 3910 | ⊕⊕⊕⊕ | Clinical or endoscopic remission defined as a mucosal score of 0 or 1 (endoscopic remission), or a bloody stool score of 0 and an UC‐DAI < 2/Simple Clinical Colitis Activity Index score of ≤ 2 points (clinical remission). |
| Failure to adhere to study medication regimen Follow‐up: 6–13 months | 73 per 1000 | 86 per 1000 | RR 1.18 | 2306 | ⊕⊕⊕⊝ | Adherence to medication regimen calculated using objective data (pill count or pharmacy data) in 6/9 studies in the analysis. 2 studies used participant self‐report to calculate adherence and 1 study did not describe how adherence was assessed. |
| Adverse event Follow‐up: 6–13 months | 490 per 1000 | 481 per 1000 | RR 0.98 | 3497 | ⊕⊕⊕⊕ | Common adverse events included flatulence, dyspepsia, abdominal pain, nausea, diarrhea, headache, nasopharyngitis, inflammation of the upper respiratory tract, gastroenteritis. dental caries, and worsening of UC. |
| Serious adverse events Follow‐up: 6–13 months | 22 per 1000 | 26 per 1000 (17 to 41) | RR 1.20 (0.77 to 1.87) | 3196 (7 studies) | ⊕⊕⊕⊝ | Serious adverse events included UC aggravation, acute pancreatitis, anal fistula, pneumonia, melena, nephrolithiasis, and hypersensitivity pneumonitis. |
| Withdrawal due to adverse events Follow‐up: 6–13 months | 14 per 1000 | 17 per 1000 | RR 1.18 | 4340 | ⊕⊝⊝⊝ | Adverse events leading to withdrawal included UC aggravation, flatulence, nausea, and abdominal distension. |
| Exclusion/withdrawal after entry Follow‐up: 6–13 months | 150 per 1000 | 148 per 1000 (127 to 172) | RR 0.99 (0.85 to 1.15) | 3737 (7 studies) | ⊕⊕⊕⊕ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; OD: once daily; RR: risk ratio; SDAI: Sutherland Disease Activity Index; UC: ulcerative colitis; UC‐DAI: Ulcerative Colitis Disease Activity Index. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to imprecision (190 events). | ||||||
| Oral 5‐ASA vs comparator 5‐ASA formulation for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: people with quiescent UC | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Comparator Oral 5‐ASA | Oral 5‐ASA | |||||
| Failure to maintain clinical or endoscopic remission Follow‐up: 6–18 months | 407 per 1000 | 439 per 1000 | RR 1.08 | 707 | ⊕⊕⊝⊝ | Clinical or endoscopic remission was defined as either the Harvey Bradshaw Index (score < 3) and by a sigmoidoscopy (score 0–1) or the absence of symptoms or the presence of only mild symptoms. |
| Failure to adhere to study medication regimen | Outcome not reported. | Not reported. | ||||
| Adverse event Follow‐up: 6–12 months | 686 per 1000 | 645 per 1000 | RR 0.94 | 357 | ⊕⊕⊝⊝ | Common adverse events included dyspepsia, abdominal pain, nausea, distension, diarrhea, headache, nasopharyngitis or respiratory infections, influenza‐like disorder, and rash. |
| Serious adverse events Follow‐up: 12 months | 109 per 1000 | 61 per 1000 (15 to 24) | RR 0.56 (0.14 to 2.22) | 95 (1 study) | ⊕⊕⊝⊝ | Serious adverse events reported included urinary tract infection, severe complication of UC, cardiac arrest, ischemic heart, fracture of the scaphoid, and spigelian hernia. |
| Withdrawal due to adverse events Follow‐up: 6–12 months | 44 per 1000 | 56 per 1000 | RR 1.25 | 457 | ⊕⊝⊝⊝ | Common adverse events leading to withdrawal included headache, lethargy, hypertension, malaise, and abdominal pain. |
| Exclusion/withdrawal after entry Follow‐up: 6–12 months | 222 per 1000 | 273 per 1000 (200 to 378) | RR 1.23 (0.90 to 1.70) | 457 (5 studies) | ⊕⊕⊕⊝ | — |
| *The basis for the assumed risk (e.g. the median control group risk across studies) come from control arm of meta‐analysis, based on included trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 5‐ASA: 5‐aminosalicylic acid; CI: confidence interval; OD: once daily; RR: risk ratio; SDAI: Sutherland Disease Activity Index; UC: ulcerative colitis. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to serious imprecision (300 events). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Failure to maintain clinical or endoscopic remission at 6–12 months Show forest plot | 8 | 1555 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.61, 0.76] |
| 1.1.1 Dose of 5‐ASA: < 1 g | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.59, 1.00] |
| 1.1.2 Dose of 5‐ASA: 1–1.9 g | 6 | 1116 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.56, 0.75] |
| 1.1.3 Dose of 5‐ASA: ≥ 2 g | 2 | 306 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.60, 0.89] |
| 1.2 Development of any adverse event at 6–12 months Show forest plot | 5 | 1132 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.73, 1.18] |
| 1.2.1 Dose of 5‐ASA: < 1 g | 1 | 133 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.51, 1.31] |
| 1.2.2 Dose of 5‐ASA: 1–1.9 g | 3 | 693 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.83, 1.08] |
| 1.2.3 Dose of 5‐ASA: ≥ 2 g | 2 | 306 | Risk Ratio (M‐H, Random, 95% CI) | 1.69 [0.14, 20.58] |
| 1.3 Development of any adverse event (sensitivity analysis) at 6–12 months Show forest plot | 4 | 1031 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.79, 1.06] |
| 1.3.1 Dose of 5‐ASA: < 1 g | 1 | 133 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.51, 1.31] |
| 1.3.2 Dose of 5‐ASA: 1–1.9 g | 3 | 693 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.83, 1.08] |
| 1.3.3 Dose of 5‐ASA: ≥ 2 g | 1 | 205 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.25, 1.12] |
| 1.4 Development of any serious adverse event at 6–12 months Show forest plot | 3 | 826 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.19, 1.84] |
| 1.4.1 Dose of 5‐ASA: < 1 g | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.03, 7.46] |
| 1.4.2 Dose of 5‐ASA: 1–1.9 g | 3 | 693 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.18, 2.15] |
| 1.5 Withdrawal from study due to adverse event at 6–12 months Show forest plot | 7 | 1454 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.76, 1.95] |
| 1.5.1 Dose of 5‐ASA: < 1 g | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.15, 13.38] |
| 1.5.2 Dose of 5‐ASA: 1–1.9 g | 5 | 1015 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.54, 1.78] |
| 1.5.3 Dose of 5‐ASA: ≥ 2 g | 2 | 306 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.80 [0.78, 4.15] |
| 1.6 Withdrawal from study due to adverse event (sensitivity analysis) at 6–12 months Show forest plot | 6 | 1353 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.50, 1.47] |
| 1.6.1 Dose of 5‐ASA: < 1 g | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.15, 13.38] |
| 1.6.2 Dose of 5‐ASA: 1–1.9 g | 5 | 1015 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.54, 1.78] |
| 1.6.3 Dose of 5‐ASA: ≥ 2 g | 1 | 205 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.07, 1.60] |
| 1.7 Exclusion/withdrawal after entry (not due to relapse) at 6–12 months Show forest plot | 5 | 1074 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.88, 1.44] |
| 1.7.1 Dose of 5‐ASA: < 1 g | 1 | 177 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.58, 1.40] |
| 1.7.2 Dose of 5‐ASA: 1–1.9 g | 3 | 591 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.87, 1.71] |
| 1.7.3 Dose of 5‐ASA: ≥ 2 g | 2 | 306 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.69, 2.29] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Failure to maintain clinical or endoscopic remission at 6–18 months Show forest plot | 12 | 1655 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [1.03, 1.27] |
| 2.2 Failure to maintain remission (trials without olsalazine) at 6–12 months Show forest plot | 7 | 749 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.92, 1.26] |
| 2.3 Development of any adverse event at 6–18 months Show forest plot | 7 | 1138 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.82, 1.40] |
| 2.4 Withdrawal from study due to adverse event at 6–18 months Show forest plot | 10 | 1585 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.87, 1.87] |
| 2.5 Exclusion/withdrawal after entry (not due to relapse) at 6–18 months Show forest plot | 9 | 1497 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [1.04, 1.63] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Failure to maintain clinical or endoscopic remission at 6 months Show forest plot | 3 | 1871 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.85, 1.23] |
| 3.1.1 Asacol (OD vs BID or TID) | 2 | 1045 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.83, 1.46] |
| 3.1.2 MMX (OD) vs Asacol (BID) | 1 | 826 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.75, 1.23] |
| 3.2 Failure to maintain clinical or endoscopic remission at 12–13 months Show forest plot | 10 | 3910 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.88, 1.01] |
| 3.2.1 Asacol (OD vs BID or TID) | 5 | 2039 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.91, 1.06] |
| 3.2.2 MMX (OD) vs Asacol (BID) | 1 | 331 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.74, 1.33] |
| 3.2.3 Pentasa (OD vs BID) | 2 | 654 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.60, 0.93] |
| 3.2.4 MMX (OD vs BID) | 1 | 451 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.87, 1.47] |
| 3.2.5 Salofalk granules (OD vs TID) | 1 | 435 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.60, 1.10] |
| 3.3 Failure to adhere to study medication regimen at study endpoint at 6–13 months Show forest plot | 9 | 2306 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.72, 1.93] |
| 3.4 Failure to adhere to study medication regimen at 6–13 months (sensitivity analysis – excluding outliers) Show forest plot | 7 | 1642 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.92, 1.62] |
| 3.5 Development of any adverse event at 6–13 months Show forest plot | 8 | 3497 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.92, 1.04] |
| 3.6 Development of serious adverse events at 6–13 months Show forest plot | 7 | 3196 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.77, 1.87] |
| 3.7 Withdrawal due to adverse event at 6–13 months Show forest plot | 8 | 4340 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.74, 1.89] |
| 3.8 Exclusion/withdrawal after entry (not due to relapse) at 6–13 months Show forest plot | 7 | 3737 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.85, 1.15] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Failure to maintain clinical or endoscopic remission at 6–18 months Show forest plot | 6 | 707 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.91, 1.28] |
| 4.1.1 Asacol comparator | 5 | 615 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.87, 1.26] |
| 4.1.2 Salofalk comparator | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.86, 1.98] |
| 4.2 Development of any adverse event at 6–12 months Show forest plot | 4 | 357 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.83, 1.07] |
| 4.2.1 Asacol comparator | 3 | 265 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.85, 1.08] |
| 4.2.2 Salofalk comparator | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.51, 1.34] |
| 4.3 Development of any serious adverse event at 12 months Show forest plot | 1 | 95 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.14, 2.22] |
| 4.3.1 Asacol comparator | 1 | 95 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.14, 2.22] |
| 4.4 Withdrawal from study due to adverse event at 6–12 months Show forest plot | 5 | 457 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.56, 2.78] |
| 4.4.1 Asacol comparator | 4 | 365 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.64 [0.61, 4.42] |
| 4.4.2 Salofalk comparator | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.16, 2.90] |
| 4.5 Exclusion/withdrawal after entry (not due to relapse) at 6–12 months Show forest plot | 5 | 457 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.90, 1.70] |
| 4.5.1 Asacol comparator | 4 | 365 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [0.81, 1.80] |
| 4.5.2 Salofalk comparator | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.76, 2.16] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Failure to maintain clinical or endoscopic remission at 6–18 months Show forest plot | 10 | 1781 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.72, 1.00] |
| 5.1.1 Asacol 4.8 g vs 2.4 g/day | 1 | 112 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.46, 1.38] |
| 5.1.2 Asacol 3.2 g vs 2 g/day | 1 | 262 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.83, 1.37] |
| 5.1.3 Asacol 2.4 g vs 1.2 g/day | 1 | 156 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.78, 1.16] |
| 5.1.4 Asacol 1.6 g vs 0.8 g/day | 1 | 177 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.78, 1.32] |
| 5.1.5 Balsalazide 6.0 g vs 3.0 g/day | 2 | 216 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.21, 2.79] |
| 5.1.6 Balsalazide 4.0 g vs 2.0 g/day | 1 | 133 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.45, 0.97] |
| 5.1.7 Olsalazine 2.0 g vs 1.0 g/day | 1 | 127 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.66, 1.54] |
| 5.1.8 Salofalk granules 3 g vs 1.5 g once daily | 1 | 429 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.49, 0.86] |
| 5.1.9 Pentasa 3.0 g vs 1.5 g/day | 1 | 169 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.48, 1.15] |
| 5.2 Development of any adverse event at 6–12 months Show forest plot | 5 | 977 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.87, 1.19] |
| 5.2.1 Asacol 2.4 g vs 1.2 g/day | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.85 [0.12, 68.95] |
| 5.2.2 Asacol 1.6 g vs 0.8 g/day | 1 | 177 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.86 [1.18, 2.95] |
| 5.2.3 Balsalazide 6.0 g vs 3.0 g/day | 1 | 88 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [0.88, 2.24] |
| 5.2.4 Olsalazine 2.0 g vs 1.0 g/day | 1 | 127 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.37 [0.94, 1.99] |
| 5.2.5 Salofalk granules 3 g vs 1.5 g once daily | 1 | 429 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.61, 0.91] |
| 5.3 Development of any serious adverse event at 6–12 months Show forest plot | 2 | 606 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.43, 2.82] |
| 5.3.1 Asacol 1.6 g vs 0.8 g/day | 2 | 606 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.43, 2.82] |
| 5.4 Withdrawal from study due to adverse event at 6–12 months Show forest plot | 7 | 1260 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.53, 1.61] |
| 5.4.1 Asacol 2.4 g vs 1.2 g/day | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.85 [0.12, 68.95] |
| 5.4.2 Asacol 1.6 g vs 0.8 g/day | 1 | 177 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.04, 3.25] |
| 5.4.3 Balsalazide 6.0 g vs 3.0 g/day | 2 | 196 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.21, 1.70] |
| 5.4.4 Balsalazide 4.0 g vs 2.0 g/day | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.54, 3.80] |
| 5.4.5 Salofalk granules 3 g vs 1.5 g once daily | 1 | 429 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.29, 3.33] |
| 5.4.6 Pentasa 3.0 g vs 1.5 g/day | 1 | 169 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.07, 16.69] |
| 5.5 Exclusion/withdrawal after entry (not due to relapse) at 6–12 months Show forest plot | 8 | 1387 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.71, 1.05] |
| 5.5.1 Asacol 2.4 g vs 1.2 g/day | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.38, 2.40] |
| 5.5.2 Asacol 1.6 g vs 0.8 g/day | 1 | 177 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.80, 1.90] |
| 5.5.3 Balsalazide 6.0 g vs 3.0 g/day | 2 | 196 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.26, 0.84] |
| 5.5.4 Balsalazide 4.0 g vs 2.0 g/day | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.77, 2.12] |
| 5.5.5 Olsalazine 2.0 g vs 1.0 g/day | 1 | 127 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [0.83, 3.70] |
| 5.5.6 Salofalk granules 3 g vs 1.5 g once daily | 1 | 429 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.46, 0.93] |
| 5.5.7 Pentasa 3.0 g vs 1.5 g/day | 1 | 169 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.44, 1.55] |
