Accepted Article

Received Date : 28-Nov-2013 Revised Date : 12-Jan-2014 Accepted Date : 14-Jan-2014 Article type

: Original Article - Randomised Controlled Trial

Isosorbide dinitrate ointment versus botulinum toxin A (Dysport®) as primary treatment for chronic anal fissure: a randomized multicentre study

A.E.M. Berkel, surgical sub-interna C. Rosman, surgeonb R. Koop, nurse practitionera c

P. van Duijvendijk, surgeon

J. van der Palen, clinical epidemiologist

d,e

a

J.M. Klaase, surgeon a

Department of Surgery, Medisch Spectrum Twente, Enschede, The Netherlands

b

c

Department of Surgery, Gelre Ziekenhuizen location Lukas, Apeldoorn, The Netherlands d

e

Department of Surgery, Canisius Wilhelmina ziekenhuis, Nijmegen, The Netherlands

Department of Epidemiology, Medisch Spectrum Twente, Enschede, The Netherlands

Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede, The Netherlands

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/codi.12615 This article is protected by copyright. All rights reserved.

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Address of correspondence Dr. J.M. Klaase, surgeon Department of Surgery Medisch Spectrum Twente Haaksbergerstraat 55 7500 KA Enschede The Netherlands Email: [email protected] Fax: 0031-53-4872526

Authorship and contributions Conception and design: J.M. Klaase Acquisition of data: A.E.M. Berkel, C. Rosman, R. Koop, P. van Duijvendijk, J.M. Klaase Data analysis and interpretation: A.E.M. Berkel, J. Van der Palen, J.M. Klaase Manuscript writing and revision: A.E.M. Berkel, C. Rosman, R. Koop, P. van Duijvendijk, J. Van der Palen, J.M. Klaase Final approval of manuscript: A.E.M. Berkel, C. Rosman, R. Koop, P. van Duijvendijk, J. Van der Palen, J.M. Klaase

Trial registration number: P04-58.

Abstract Background: Nitric oxide donors, such as isosorbide dinitrate ointment (ISDN), are considered as first choice agents in the treatment of chronic anal fissure. Injection with botulinum toxin A in the internal anal sphincter is often used as second-line therapy, although it may give better results and fewer side effects than nitric oxide donors. The aim of this randomized clinical trial was to investigate whether botulinum toxin A (Dysport®) is more effective than ISDN in the primary treatment of chronic anal fissure.

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Accepted Article

Methods: In the period April 2005 until October 2009, 60 patients (32 male) with a median age of 42 (25-82) years were randomized to receive either ISDN 10 mg/mL (1%) (n=33) or injection with 60 units Dysport® (n=27). The primary endpoint was the percentage complete fissure healing after 8 weeks. Results: After a median of 9 weeks complete fissure healing was noted in 18 of 27 patients in the Dysport® group and in 11 of 33 patients in the ISDN group (p=0.010). Absolute improvement of pain scores after 9 weeks was similar in both groups (p=0.733). Patients treated with Dysport® had fewer side effects than patients treated with ISDN (p=0.028). Of the patients with a healed fissure, 28% of the Dysport® group and 50% of the ISDN group had a recurrence within one year (p=0.286; HR 2.08; 95% CI=0.54-7.97). Conclusion: Dysport® is more effective with fewer side effects than ISDN ointment in the primary treatment of chronic anal fissure. The recurrence rates within one year in both treatment groups is high.

What does this paper add to the literature? In the literature there are only a few randomized controlled trials that compared botulinum toxin A with ISDN in the primary treatment of chronic anal fissure. This multicentre randomized controlled trial has shown greater benefit for the former over the course of one year.

Introduction An acute anal fissure typically heals within six weeks with conservative local management, while a chronic anal fissure exits for more than six weeks with features of chronicity and requires a more aggressive approach[1-3]. The aetiology is not well understood, but increased anal pressure due to increased the internal anal sphincter activity is likely to play a role in the pathophysiology[4,5]. Internal sphincter hypertonia compresses the end arteries passing through the internal sphincter causing ischaemia of the anoderm of the posterior commissure, resulting in failure of healing [6,7]. The goal of therapy is to diminish sphincter spasm and thereby to restore blood flow to the anodermis, encouraging healing of the fissure [2]. Historically the most common approach was surgical including procedures such as manual anal dilation and lateral sphincterotomy, but given the risk of a disturbance in faecal continence, the treatment has shifted towards pharmacological therapy. Nitric oxide (NO) donors such as isosorbide dinitrate ointment (ISDN) or glyceryl trinitrate (GTN), are considered as first line agents, because of the safety, simple application and low cost. Healing following their use varies from 30-93% after two months treatment[8,9], but headache may cause the patient to discontinue treatment[4,8]. The need to apply the agent frequently owing to its short action is another disadvantage and can also lead to reduced patient compliance. More recently, the injection of botulinum toxin A in the internal anal sphincter has been used often as secondline therapy. Brisinda et al [10] conducted a randomized controlled trial comparing botulinum toxin with topical

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Accepted Article

nitroglycerine and found the former to be more effective after two mont hs. Botulinum toxin A injection temporarily reduces anal resting pressure by blocking the acetylcholine release in the internal sphincter [1,11,12]. The healing rate of botulinum toxin A at two months varies from 68-96%[10,13]. Advantages of botulinum toxin A injection over NO donors include better patient compliance, because the treatment consists of one single injection and fewer side effects[1,10,11,14]. In 2007 we showed in a prospective trial that Dysport® is effective in patients with ISDN ointment-resistent chronic anal fissure (n=100)[6]. In the present randomized controlled trial we set out to determine whether it is more effective than ISDN in the primary treatment of chronic anal fissure.

Method All consecutive patients of 18 years or older presenting with a chronic anal fissure between April 2005 and October 2009 were eligible for inclusion in a randomized multicentre study. The fissure was considered chronic if the patient had an ulcer posterior or anterior for more than six weeks and/or a fissure with clinical signs of chronicity (indurated edges, sentinel pile, visible fibers of the internal anal sphincter, hypertrophied anal papilla). Exclusion criteria were acute fissure (present for

Isosorbide dinitrate ointment vs botulinum toxin A (Dysport) as the primary treatment for chronic anal fissure: a randomized multicentre study.

Nitric oxide donors, such as isosorbide dinitrate ointment (ISDN), are considered as first-choice agents in the treatment of chronic anal fissure. Inj...
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