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Topical diltiazem and glyceryl-trinitrate for chronic anal fissure: A meta-analysis of randomised controlled trials.

INTRODUCTION

Anal fissure is a lineal tear in the anal canal distal to the dentate line (1). Chronic anal fissure (CAF) is associated with hypertonia of the internal sphincter resulting in mucosal ischaemia and failure to heal, which results in severe anal pain (2,3). Resolution of the symptoms can be achieved by lowering the resting anal tone, and increasing blood flow. Historically, this was achieved by division of the muscle fibers, in the form of a lateral sphincterotomy. This was the mainstay of treatment, however, lateral sphincterotomy causes significant morbidity with reported incontinence rates of up to 30% (4).

Topical treatment of CAF with Diltiazem (DTZ) and Glyceryl-trinitrate (GTN) can result in good outcome, without the risk of surgery and incontinence. In the UK, topical GTN is considered first line therapy for CAF, and clinicians are advised to use analgesics concurrently for the management of side effects such as headache, DTZ is only considered after this (5). This meta-analysis of randomized controlled trials (RCTs) aimed to assess healing, headache and recurrence rates of CAF in adult patients treated with topical DTZ and GTN.

MATERIAL and METHODS

The search engines Ovid Medline, Embase, PubMed, Scopus and Google Scholar were used to identify publications. Search terms used were "chronic anal fissure" "glyceryl-trinitrate", "diltiazem', "healing," "side effect," "randomized" in exploded and linked combinations. Complete articles published in English since January 2000 were considered for inclusion. Articles identified were RCTs which compared out-comes of topical DTZ vs topical GTN in the management of CAF. All articles pertaining to acute anal fissure, systemic therapies, or surgical therapies were excluded. This search strategy is summarized in Figure 1. Primary outcomes included rates of healing, headaches and reported recurrence, which were collected by a single author (EJN).

A meta-analysis was performed by combining the results of outcome variables. Data were summarized using risk ratio. Heterogeneity among the studies was estimated using chi-squared ([chi square]) tests which were reported as the [I.sup.2] statistic to estimate the percentage of total variation across studies attributable to study heterogenicity. A random effects meta-analysis model was used to account for the possible clinical diversity and methodological variation amongst the studies. All p-values were 2-sided. A significant difference was defined as p< 0.05. Statistical analysis was conducted with Review Manager Version 5.3 (Cochrane Collaboration, Software Update, Oxford, UK).

Ethical approval for this research was not required owing to it being a meta-analysis of previously published (and approved) RCTs.

RESULTS

A total of 9 RCTs were identified, they incorporated 385 patients who were treated with DTZ and 371 in the GTN group (Table 1). All studies used between 6 and 12 weeks of treatment using 2% DTZ and 0.2% or 0.5% GTN twice daily. Follow up ranged from 6 weeks to 52 weeks following completion of treatment.

Across the 9 studies, 277/379 (73.1%) of the patients treated with DTZ had healed. A total of 244/351 (69.5%) of the patients treated with GTN had healed. There was therefore no significant difference in healing rates between the two groups (p= 0.48) (Figure 2).

Eight studies reported rates of headaches during treatment. Only 31/359 (8.6%) of those treated with DTZ reported headache. The rates of headache in those treated with GTN was significantly worse, 208/335 (62.1%) (p< 0.0001) (Figure 3).

Four RCTs reviewed late recurrence rates (>12 weeks) of CAF following completion of treatment. Recurrence rates were higher in the group treated by GTN compared to DTZ, 23/123 (18.7%) vs 13/143 (9.1%) respectively (p= 0.04) (Figure 4).

DISCUSSION

Due to the risk of fecal incontinence and the financial cost of operative management, there has been a shift from operative intervention for the treatment of CAF to non-operative treatment modalities. Surgery is now typically reserved for treatment resistant CAF (15). Moreover, systemic therapy for CAF is poorly tolerated due to side effects (2,16). For this reason topical therapies, with low side effect profiles, have been assessed.

Nine RCTs published since 2000 have been identified which compared topical DTZ and GTN. This meta-analysis has demonstrated comparable healing rates with DTZ (73.1%) when compared to GTN (69.5%). However, recurrence rates were twice as high in the GTN group. Moreover, rates of headache were significantly higher in the GTN cohort. Furthermore, Ala et al. have demonstrated faster symptom resolution with DTZ when compared to GTN (12). All of these reasons point towards the use of DTZ as first line therapy for the topical management of CAF. This report validates previously published reviews which have also demonstrated favorable outcomes with topical DTZ rather than GTN (17,18).

Importantly, the NHS drug tariff for DTZ is less than that for GTN. The tariff for DTZ cream is [pounds sterling]17.59 (DTZ 2% cream 30 g), and DTZ ointment is even less, [pounds sterling]13.44 (DTZ 2% ointment 30 g). 0.4% GTN ointment (Rectogesic 30 g) is significantly more expensive and costs [pounds sterling]39.30 (19). This should be considered as another reason for considering DTZ as first line therapy.

Limitations

This meta-analysis has reviewed all randomized controlled trials reviewing DTZ and GTN for CAF. All publications used very similar treatment regimens (Table 1); however, not all publications reported a standard definition for CAF, this may be one of the reasons for the slight variation in reported results across studies.

In addition, RCTs included in the present analysis used either 0.5% or 0.2% GTN. All 8 RCTs that compared rates of headache demonstrated favorable outcomes in the DTZ group. Therefore, we believe that even the lower dose preparation is less likely to be tolerated when compared to DTZ. It is, however, possible that this dose variability may have impacted upon other outcomes in the present analysis, such as recurrence or healing. Nevertheless, two previously published RCTs have failed to demonstrate that increasing concentrations of GTN affect healing rates in CAF (20,21).

Despite all of the trials included in this study being RCTs, there remains significant risk of bias (Table 1). Only 3 of the studies reported if the assessors or patients were blinded; and we must therefore assume that the rest were not, therefore there is significant risk of observer bias in these trials. Two also failed to report their randomization methods, which again questions their validity. Furthermore, only 2 publications report their funding sources.

CONCLUSION

This meta-analysis has identified comparable healing rates for DTZ and GTN. However, DTZ results in fewer headaches and fewer late recurrences. DTZ should therefore be considered as first line non-operative treatment for chronic anal fissure.

Ethics Committee Approval: Ethical approval for this research was not required owing to it being a meta-analysis of previously published (and approved) RCTs.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - E.J.N., V.K.; Design - E.J.N., V.K.; Supervision - E.J.N., V.K.; Resource - E.J.N., V.K.; Data Collection and/or Processing - E.J.N., V.K.; Analysis and Interpretation - E.J.N., V.K.; Literature Review - E.J.N., V.K.; Writing Manuscript - EJ.N., V.K.; Critical Reviews - EJ.N., V.K.

Conflict of Interest: The authors declare that they have no conflict of interest.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES

(1.) Knight JS, Birks M, Farouk R. Topical diltiazem ointment in the treatment of chronic anal fissure. Br J Surg 2001; 88:553-6. [CrossRef]

(2.) Carapeti EA, Kamm MA, Phillips RKS. Topical diltiazem and bethanechol decrease anal sphincter pressure and heal anal fissures without side effects. Dis Colon Rectum 2000; 43:1359-62. [CrossRef]

(3.) Lund JN, Scholefield JH. Aetiology and treatment of anal fissure. Br J Surg 1996; 83:1335-44. [CrossRef]

(4.) Garcfa-Aguilar J, Montes CB, PerezJJ, Jensen L, MadoffRD, Wong WD. Incontinence after Lateral internal sphincterotomy: Anatomic and functional evaluation. Dis Colon Rectum 1998; 41:423-7. [CrossRef]

(5.) Natl Institue Heal Care Excel! Anal Fissure. 2017 [cited 2020Jun 3]. Available from: https://cks.nice.org.uk/anal-fissuretiscenario [CrossRef]

(6.) Bielecki K, Kolodziejczak M. A prospective randomized trial of diltiazem and glyceryltrinitrate ointment in the treatment of chronic anal fissure. Color Dis 2003; 5:256-7. [CrossRef]

(7.) Kocher HM, Steward M, Leather AJM, Cullen PT. Randomized clinical trial assessing the side-effects of glyceryl trinitrate and diltiazem hydrochloride in the treatment of chronic anal fissure. Br J Surg 2002; 89: 413-7. [CrossRef]

(8.) Shrivastava UK, Jain BK, Kumar P, Saifee Y. A comparison of the effects of diltiazem and glyceryl trinitrate ointment in the treatment of chronic anal fissure: a randomized clinical trial. Surg Today 2007; 37:482-5. [CrossRef]

(9.) Jawaid M, Masood Z, Salim M. Topical diltiazem hydrochloride and glyceryl trinitrate in the treatment of chronic anal fissure. J Coll Physicians Surg Pak2009; 19:614-7. [CrossRef]

(10.) Sanei B, Mahmoodieh M, Masoudpour H. Comparison of topical glyceryl trinitrate with dialtazem ointment for treatment of chronic anal fissure. A randomized clinical trial. Ann Ital Chir 2009; 80:379-83. [CrossRef]

(11.) Suvarna R, Hunamanthappa M, Panchami, Rai G. Topical diltiazem versus topical glyceryl trinitrate (GTN) in the treatment of chronic anal fissure: prospective study. Int J Biol Med Res 2012; 3:1747-50. [CrossRef]

(12.) Ala S, Saeedi M, Hadianamrei R, Ghorbanian A. Topical Diltiazem vs. topical Glyceril trinitrate in the treatment of chronic anal fissure: a prospective, randomized, double-blind trial. Acta Gastroenterol Belg 2012; 438-42. [CrossRef]

(13.) Bansal AR, Kumar Yadav P, Godara R, Pal N, Tripura R, Jaikaran. Comparative evaluation of 0.2% glyceryl trinitrate vs. 2% diltiazem ointment in treatment of chronic anal fissure treatment -a randomized trial. Hell J Surg 2016; 88:25-30. [CrossRef]

(14.) Venkatesh S, Kulkarni SB, Kruthi SR. Topical diltiazem versus topical glyceryl trinitrate in the treatment of chronic anal fissure: a prospective comparative study. Int Surg J 2019;6. [CrossRef]

(15.) Nelson RL, Thomas K, Morgan J, Jones A. Non surgical therapy for anal fissure. Cochrane Database Syst Rev 2012; 2012(2): CD003431. [CrossRef]

(16.) Cook TA, Smilgin Humphreys MM, McC Mortensen NJ. Oral nifedipine reduces resting anal pressure and heals chronic anal fissure. Br J Surg 1999;86:1269-73. [CrossRef]

(17.) Nelson RL, Manuel D, Gumienny C, Spencer B, Patel K, Schmitt K, et al. A systematic review and meta-analysis of the treatment of anal fissure. Tech Coloproctol2017; 605-25. [CrossRef]

(18.) Sajid MS, Whitehouse PA, Sains P, Baig MK. Systematic review of the use of topical diltiazem compared with glyceryltrinitrate for the no-noperative management of chronic anal fissure. Color Dis 2013; 15: 19-26. [CrossRef]

(19.) National Health Service England and Wales Electronic Drug Tariff [Internet], 2020. Available from: www.drugariff.nhsbsa.nhs.uk/t/00774110-DC/DC00774097/Home [CrossRef]

(20.) Scholefield JH, Bock JU, Marla B, Richter HJ, Athanasiadis S, Prols M, et al. A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures. Gut 2003; 52:264-9. [CrossRef]

(21.) Bailey HR, Beck DE, Billingham RP, Binderow SR, Gottesman L, Hull TL, et al. A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures. Dis Colon Rectum 2002; 45:1192-9. [CrossRef]

ORIJINAL CALISMA-OZET

Kronik anal fissur tedavisinde topikal diltiazem ve gliseril-trinitrat: Randomize kontrollu calismalarin meta-analizi

Edward J Nevins (1), Venkatesh Kanakala (1)

(1) NHS Vakfi South Tees Hastaneleri, Genel Cerrahi Klinigi, Middlesbrough, Ingiltere

OZET

Giris ve Amac: Kronik anal fissurun cerrahi tedavisi kalici fekal enkontinansa neden olabilir. Topikal tedavilerde ciddi komplikasyon riski daha dusuktur ve bu tedaviler cerrahi mudahaleden daha ucuzdur. Literaturde topikal ajanlarla iyilesme ve uyum oranlari degisiklik gostermektedir. Bu calismanin amaci, topikal diltiazem (DTZ) ve topikal gliseril-trinitrat (GTN) ile tedavi edilen hastalarda iyilesme oranlarini, bas agrisi vakalari ve kronik anal fissur nuks oranlarini birinci basamak non-operatif tedaviler kapsaminda karsilastirmaktir.

Gerec ve Yontem: Ocak 2000'den beri yayimlanan, kronik anal fissur tedavisi icin topikal DTZ ve GTN'yi karsilastiran randomize kontrollu calismalar (Randomized Controlled Trials) tespit edilerek karsilastirilmistir. Karsilastirma noktalari iyilesme oranlari, tedaviye bagli bas agrisi ve gec nuks etme (> 12 hafta) olarak belirlenmistir. Sonuclari karsilastirmak icin bir randomize meta-analiz modeli kullanilmistir.

Bulgular: Tum calismalarda %2 DTZ ve %0,2 veya %0,5 GTN kullanilmistir ve tedavi 6-12 hafta boyunca gunde iki kez uygulanmistir. Dokuz calismanin topikal DTZ (n= 379) ve GTN (n= 351) ile iyilesme oranlari karsilastirildiginda, iki grup arasinda fark olmadigi gorulmustur (RR 1,04 [0,93-1,16], p= 0,48). Bas agrisi vakalarinin incelendigi 8 calismada, DTZ'nin daha iyi tolere edildigi gorulmustur (RR 0,15 [0,07-0,34], p< 0,00001). Gec nuksetme oranlarinin karsilastirildigi 4 calismada, DTZ'nin daha iyi oldugu tespit edilmistir (RR 0,51 [0,27-0,96], p= 0,04).

Sonuc: Her ne kadar Topikal DTZ ve GTN arasinda iyilesme oranlari arasinda bir fark olmasa da bas agrisi ve gec nuksetme degiskenlerinde DTZ'nin daha iyi oldugu gorulmustur. Bu nedenle DTZ, kronik anal fissur icin birinci basamak non-operatif tedavi olarak dusunulmelidir.

Anahtar Kelimeler: Kronik anal fissur, topikal tedavi, diltiazem, gliseril trinitrat

DOI: 10.47717/turkjsurg.2020.4895

Edward J Nevins (1) (iD), Venkatesh Kanakala (1) (iD)

(1) South Tees Hospitals Nhs Foundation Trust, Clinic of General Surgery, Middlesbrough, United Kingdom

Cite this article as: Nevins EJ, Kanakala V. Topical diltiazem and glyceryl-trinitrate for chronic anal fissure: A meta-analysis of randomised controlled trials. Turk J Surg 2020; 36 (4): 347-352.

Corresponding Author Edward J Nevins

E-mail: dr.e.nevins@gmail.com

Received: 31.08.2020

Accepted: 19.09.2020

Available Online Date: 29.12.2020

[c] Copyright 2020 by Turkish Surgical Society Available online at www.turkjsurg.com

DOI: 10.47717/turkjsurg.2020.4895
Table 1. Data extracted from RCTs comparing GTN and DTZ for CAF

Author                DTZ    GTN    Treatment  Follow   Blinding
                      group  group  length     up

Bielecki 2002 (5)      22     21    BD 8/52    8/52     ?
Kocher 2002 (6)        31     29    BD 6-8/25  12/52    Double
Shrivastava 2006 (7)   30     30    BD 6/25    3/12     ?
Jawaid 2009 (8)        40     40    BD 8/52    8/52     ?
Sanei 2009 (9)         51     51    BD 12/52   8-12/52  Double
Suvarna 2010 (10)     100    100    BD 6/52    52/52    ?
Ala 2012 (11)          36     25    BD 8/52    8/52     Double
Bansal 2016 (12)       25     25    BD 6/52    3/12     ?
Venkatesh 2019 (13)    50     50    BD 8/52    6/52     ?
Total                 385    371

Author                Randomisation       Source of
                      protocol            funding

Bielecki 2002 (5)                         ?
Kocher 2002 (6)       Computer generated  ?
Shrivastava 2006 (7)  Drawing lots        ?
Jawaid 2009 (8)       Computer generated  ?
Sanei 2009 (9)        Computer generated  ?
Suvarna 2010 (10)     Sequential order    None
Ala 2012 (11)         Computer generated  ?
Bansal 2016 (12)      Computer generated  ?
Venkatesh 2019 (13)   ?                   None
Total

?: Paper does not specify.
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Title Annotation:ORIGINAL ARTICLE
Author:Nevins, Edward J.; Kanakala, Venkatesh
Publication:Turkish Journal of Surgery
Article Type:Report
Geographic Code:4EUUK
Date:Dec 1, 2020
Words:2429
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