Chronic anal fissure: 0.2% topical glyceryl trinitrate ointment

Efficacy

The Cochrane review (75 studies, 5031 patients) of non-surgical therapy for anal fissure included a total of 18 RCTs in 1315 people, mostly adults, involving glyceryl trinitrate. It found that, overall, glyceryl trinitrate (pooled strengths, range unclear) was marginally, but statistically significantly, better than placebo in healing chronic anal fissure (48.9% compared with 35.5%, p<0.0009) but late recurrence was common, occurring in approximately 50% of people whose fissures were initially cured. Of interest for this evidence summary, it pooled results from 4 RCTs to compare 'high' and 'low' strengths of topical glyceryl trinitrate ointment to treat chronic anal fissure in adults and children (n=324 analysed). High and low cut-offs were not defined in the review but glyceryl trinitrate ointment strengths in the individual trials ranged from 0.05% to 0.6%. The meta-analysis found no significant difference in fissure healing between the different strengths of glyceryl trinitrate used (low strength compared with high strength pooled odds ratio [OR] 0.91, 95% confidence interval [CI] 0.57 to 1.45).

This Cochrane review did not report a direct comparison of topical 0.2% with 0.4% glyceryl trinitrate, and no pooled estimate of effect was reported for the outcomes of pain reduction or adverse events due to headaches. The RCTs that were included in the Cochrane review for glyceryl trinitrate strength comparison are discussed below.

Key outcomes for 2 of the RCTs (Scholefield et al. 2003 and Carapeti et al. 1999) are summarised in tables 1 and 2 respectively. The RCT by Bailey et al. (2002) is not included in the tables because it presented most of its key outcomes in a graphical format only, therefore exact figures were not available. The RCT by Simpson et al. (2003) is not included in the tables because it did not use 0.2% or 0.4% glyceryl trinitrate ointment.

Children

No evidence was identified to assess the efficacy or safety of using 0.2% glyceryl trinitrate ointment in children and young people under 18 years. Only 1 pilot RCT (n=15) was identified but this used 0.1% and 0.05% glyceryl trinitrate ointment (Simpson et al. 2003). The authors' rationale for using these lower strength ointments was that the optimum therapeutic strength of glyceryl trinitrate ointment had not been established.

Adults

No studies were identified that were designed specifically to compare the efficacy of 0.2% with 0.4% glyceryl trinitrate ointment for chronic anal fissure, such as an RCT sufficiently powered to detect these differences or a non-inferiority trial.

Three small RCTs (Scholefield et al. 2003, Carapeti et al. 1999 and Bailey et al. 2002) were identified that tested different strengths of glyceryl trinitrate (0.1%, 0.2%, 0.4% and 0.2%–0.6% escalating weekly by 0.1%) against placebo in adults with chronic anal fissure. All included a local twice-daily application of glyceryl trinitrate ointment for 8 weeks and the primary outcome in all studies was fissure healing. This was assessed at 8 weeks in Scholefield et al. (2003) and Bailey et al. (2002) and at 10 weeks (8 weeks treatment, 2 weeks after treatment) in Carapeti et al. (1999). However, no statistical tests were carried out to assess differences between the glyceryl trinitrate strengths for this primary outcome.

One RCT (Carapeti et al. 1999) attempted to assess for statistically significant differences in secondary outcomes between glyceryl trinitrate strengths (table 2). However, it was small (n=70) and was not statistically powered to detect anything but large differences between glyceryl trinitrate strengths.

Indirect comparisons from 2 small RCTs (Scholefield et al. 2003 and Carapeti et al. 1999; tables 1 and 2, only 47 and 23 adults respectively were analysed in the 0.2% ointment groups in each trial) provided very limited evidence that 0.2% glyceryl trinitrate ointment might be as effective as 0.4% glyceryl trinitrate at healing anal fissure after an 8-week treatment period in adults. However, in 1 of these (Scholefield et al. 2003), neither strength showed a statistically significant difference from placebo in healing rate.

The 3 RCTs reported relatively high healing rates in placebo arms after 8 weeks (32% [7/22] in Carapeti et al. 1999, 37.5% [18/48] in Scholefield et al. 2003 and 50% [patient numbers not reported] in Bailey et al. 2002) suggesting a high spontaneous healing rate. In Scholefield et al. (2003), placebo healing rate reduced from 37.5% (18/48) to 24.3% (9/37) when a stricter definition of chronicity was used. Therefore, heterogeneity in chronic fissure definition may influence reported fissure healing rates.

Using the stricter definition of chronicity, Scholefield et al. (2003) found statistically significantly higher healing rates after 8 weeks in people using 0.1% glyceryl trinitrate ointment (50.0%, 21/42, p=0.05) and 0.4% ointment (56.7%, 17/30, p=0.03) compared with placebo (24.3%, 9/37) and for the trend of all glyceryl trinitrate groups combined compared with placebo (p=0.03). However, the 0.2% glyceryl trinitrate group on its own did not show statistically significant differences from placebo (36.1%, 13/36, p=0.91).

Table 1 Summary of the trial: Scholefield et al. (2003)

Table 2 Summary of trial: Carapeti et al. (1999)

Safety

One small RCT (Scholefield et al. 2003, 181 adults analysed) provided limited evidence that lower glyceryl trinitrate ointment strength was associated with fewer reported headaches over an 8-week treatment period in adults. It showed a statistically significant trend linking increasing glyceryl trinitrate strength (0.1%, 0.2% and 0.4% used) to more frequently reported headache. Frequency of reported headache (baseline to 8 weeks) was 12.5% (6/48) with placebo, 18.3% (9/49) with 0.1% glyceryl trinitrate, 36.1% (17/47) with 0.2% glyceryl trinitrate, and 67.5% (25/37) with 0.4% glyceryl trinitrate (p value for trend less than 0.01).

No statistical test for trend was reported comparing glyceryl trinitrate strength with the frequency of severe headaches reported in the same trial. The frequency of severe headache was 4.2% (2/48) with placebo, 2.0% (1/49) with 0.1% glyceryl trinitrate, 6.4% (3/47) with 0.2% glyceryl trinitrate, and 24.3% (9/37) with 0.4% glyceryl trinitrate.

It is not known whether applying less ointment of the same strength, rather than reducing the strength of ointment applied, might have an effect on the incidence or headache.

Cost effectiveness and cost

NHS electronic drug tariff (January 2013) data indicate that (unlicensed) 0.2% glyceryl trinitrate rectal ointment costs £57.75 for the minimum 30 g volume and an extra £1.62 for every extra gram above 30 g. The price listed for Rectogesic (0.4% glyceryl trinitrate, 4 mg/g rectal ointment, ProStrakan) is lower at £34.80 for 30 g.

No studies were identified that assessed cost effectiveness of 0.2% glyceryl trinitrate ointment compared with 0.4% glyceryl trinitrate ointment.