Botulinum Toxin Injection Plus Topical Diltiazem for Chronic Anal Fissure: A Randomized Double-Blind Clinical Trial and Long-term Outcome

Abstract

BACKGROUND: Chemical sphincterotomy avoids the risk of permanent incontinence in the treatment of chronic anal fissure, but it does not reach the efficacy of surgery and recurrence is high. Drug combination has been proposed to overcome these drawbacks. OBJECTIVE: This study aimed to compare the clinical, morphological, and functional effects of combined therapy with botulinum toxin injection and topical diltiazem in chronic anal fissure and to assess the long-term outcome after healing. DESIGN: This is a randomized, controlled, double-blind, 2-arm, parallel-group trial with a long-term follow-up. SETTINGS: This study was conducted at a tertiary care center. PATIENTS: A total of 70 consecutive patients were referred to the gastroenterology department of a hospital in Valencia, Spain. INTERVENTION: After botulinum toxin injection (20 IU), patients were randomly assigned to local diltiazem (diltiazem group) or placebo gel (placebo group) for 12 weeks. MAIN OUTCOME MEASURES: The primary outcome was fissure healing (evaluated by video register by 3 independent physicians). Secondary outcomes included symptomatic relief (30-day diary), effect on anal sphincters (manometry), safety, and long-term recurrence (24 months and 10 years). RESULTS: Healing was achieved per protocol in 13 of 25 (52%) patients of the diltiazem group and 11 of 30 (36.7%) patients of the placebo group (p = 0.25); on an intention-to-treat basis in 37.1% and 31.4% (p = 0.61). Both groups displayed significant reduction of anal pressures. Thirty percent reported minor and transitory incontinence, without differences between groups. Nine (69.2%) of the diltiazem group and 6 (54.5%) of the placebo group experienced a relapse at 24 months (p = 0.67). The overall recurrence rate at 10 years was 83.3% (20/24 patients). LIMITATIONS: This study was limited by the loss of patients during the trial. The low healing rate led to a small cohort to assess recurrence. CONCLUSIONS: Combined botulinum toxin injection and topical diltiazem is not superior to botulinum toxin injection in the treatment of chronic anal fissure. Both options offer suboptimal healing rates. Long-term recurrence is high (>80% at 10 years) and might appear at any time after healing. See Video Abstract at http://links.lww.com/DCR/B527. INYECCIÓN DE TOXINA BOTULÍNICA MÁS DILTIAZEM TÓPICO EN FISURA ANAL CRÓNICA: UN ENSAYO CLÍNICO ALEATORIZADO DOBLE CIEGO Y RESULTADOS A LARGO PLAZO ANTECEDENTES: La esfinterotomía química evita el riesgo de incontinencia permanente en el tratamiento de la fisura anal crónica, pero no alcanza la eficacia de la cirugía y la recurrencia es alta. Se ha propuesto la combinación de fármacos para superar estos inconvenientes. OBJETIVO: Comparar los efectos clínicos, morfológicos y funcionales de la terapia combinada con inyección de toxina botulínica y diltiazem tópico en fisura anal crónica y evaluar el resultado a largo plazo después de la cicatrización. DISEÑO: Ensayo aleatorizado, controlado, doble ciego, de dos brazos, de grupos paralelos con un seguimiento a largo plazo. ESCENARIO: Estudio realizado en un centro de atención terciaria. PACIENTES: Un total de 70 pacientes consecutivos referidos al servicio de gastroenterología de un hospital de Valencia, España. INTERVENCIÓN: Después de la inyección de toxina botulínica (20UI), los pacientes fueron asignados al azar a diltiazem local (grupo de diltiazem) o gel de placebo (grupo de placebo) durante 12 semanas. PRINCIPALES MEDIDAS DE RESULTADO: El resultado primario fue la cicatrización de la fisura (evaluado por registro de video por tres médicos independientes). Los resultados secundarios incluyeron alivio sintomático (diario de 30 días), efecto sobre los esfínteres anales (manometría), seguridad y recurrencia a largo plazo (24 meses y 10 años). RESULTADOS: La curación se logró por protocolo en 13/25 (52%) en el grupo de Diltiazem y 11/30 (36,7%) en el grupo de Placebo (p = 0.25); por intención de tratar en el 37.1% y el 31.4%, respectivamente (p = 0.61). Ambos grupos mostraron una reducción significativa de las presiones anales. El 30% refirió incontinencia leve y transitoria, sin diferencias entre grupos. 9 (69.2%) del grupo de Diltiazem y 6 (54.5%) del grupo de placebo recurrieron a los 24 meses (p = 0.67). La tasa global de recurrencia a los 10 años fue del 83.3% (20/24 pacientes). LIMITACIONES: La pérdida de pacientes a lo largo del ensayo. La baja tasa de curación llevó a una pequeña cohorte para evaluar la recurrencia. CONCLUSIONES: La inyección combinada de toxina botulínica y diltiazem tópico no es superior a la inyección de TB en el tratamiento de la fisura anal crónica. Ambas opciones ofrecen tasas de curación subóptimas. La recurrencia a largo plazo es alta (> 80% a los 10 años) y puede aparecer en cualquier momento después de la curación. Consulte Video Resumen en http://links.lww.com/DCR/B527.

High Recurrence Rate After Nonsurgical Treatment of Chronic Anal Fissure: Can It Be Prevented?

“…1 However, it is pertinent to note that all treatments (local diltiazem, botulinum toxin injection, and surgery) aim to decrease the anal sphincter tone. 1 These treatments are rational in the acute fissure with moderate-severe anal spasm. However, once the majority of recurrences are occurring after complete fissure healing, adequate attention should be paid to remove the main cause (chronic constipation) to prevent fissure from recurring.…”

“…Herreros et al 1 published an excellent study demonstrating the long-term outcome after nonsurgical management of chronic anal fissure (CAF).…”

“…No doubt, this makes surgery look like a better option. 1 However, it is pertinent to note that all treatments (local diltiazem, botulinum toxin injection, and surgery) aim to decrease the anal sphincter tone. 1 These treatments are rational in the acute fissure with moderate-severe anal spasm.…”

Trends in Management of Anal Fissures

“…2 However, outcomes such as pain control, healing time, incontinence, and recurrence vary widely in the literature. [3][4][5] Additionally, many of the studies regarding these strategies have a low sample size or are small institutional studies or case series and do not use validated measures to report outcomes, particularly in terms of quality of life and bowel function. 4,6 The optimal treatment strategy for an individual patient is therefore not suggested by high-quality evidence, so there is considerable discretion on the part of the treating physician.…”

Reply

“…We thank Dr Garg for the interest in our study about the long-term outcome after nonsurgical management of chronic anal fissure (CAF). 1 Regarding the high recurrence rate after healing, his comments emphasize the relevance of the management of constipation as the main factor to prevent fissure relapse. In a previous study, including patients with CAF that was healed after intrasphincteric injection of botulinum toxin and followed up for 4 years, we described an acute episode of constipation certainly related to the onset of a recurrence in 9 of 22 patients (41%).…”