Cost considerations in the treatment of anal fissures.

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Cost considerations in the treatment of anal fissures Expert Rev. Pharmacoecon. Outcomes Res. 14(4), 511–525 (2014)

Giuseppe Brisinda*, Giuseppe Bianco, Nicola Silvestrini and Giorgio Maria Department of Surgery, Catholic School of Medicine, University Hospital “Agostino Gemelli”, Largo Agostino Gemelli 8, 00168, Rome, Italy *Author for correspondence: Tel.: +39 063 015 4199 Fax: +39 063 015 6086 [email protected]

Anal fissure is a split in the lining of the distal anal canal. Lateral internal sphincterotomy remains the gold standard for treatment of anal fissure. Although technique is simple and effective, a drawback of this surgical procedure is its potential to cause minor but some times permanent alteration in rectal continence. Conservative approaches (such as topical application of ointment or botulinum toxin injections) have been proposed in order to treat this condition without any risk of permanent injury of the internal anal sphincter. These treatments are effective in a large number of patients. Furthermore, with the ready availability of medical therapies to induce healing of anal fissure, the risk of a first-line surgical approach is difficult to justify. The conservative treatments have a lower cost than surgery. Moreover, evaluation of the actual costs of each therapeutic option is important especially in times of economic crisis and downsizing of health spending. KEYWORDS: anus • autonomic nervous system disease • botulinum toxin • calcium channel blockers • cost analysis • evidence-based medicine • fissure-in-ano • lateral internal sphincterotomy • surgery

Anal fissure (AF) is a distressing condition [1]. The etiology of chronic AF remains controversial, although spasm of the internal anal sphincter (IAS) has been recognized to play a central role in the pathogenesis of the disease [2–4]. Surgical sphincterotomy, which is widely performed to provide symptomatic relief and healing, is highly effective but can be associated with permanent complications [5]. Several reports confirm that the management of AF has undergone extensive re-evaluation with renewed emphasis during the past few years. This rejuvenation of interest is attributable to the application of alternative treatment (such as topical ointment or injection of botulinum toxin [BT]) [6–10], which has contributed to the tendency to treat the disease on an outpatient procedure basis. Alternative approaches have been proposed in order to treat this condition without any risk of permanent IAS injury. Furthermore, with the ready availability of medical therapies, the risk of a fist-line surgical approach is difficult to justify [11]. These treatments are effective in a large number of patients. On the other hand, conservative treatments have a lower cost than surgery. We report in this paper the most recent findings on the conservative treatment of chronic AF. Furthermore, we have assessed the costs related to the treatment informahealthcare.com

10.1586/14737167.2014.924398

of patients with chronic AF. We believe that the evaluation of the actual costs of each therapeutic option is dramatically important, especially in times of downsizing of health spending due to economic crisis. Etiology & diagnosis

AF is a split in the skin of the distal anal canal. It is a common problem that causes significant complications in a young and otherwise healthy population, with a roughly equal incidence in both sexes [9,12]. Most AFs are acute and relatively short-lived. The distinction between acute and chronic AF is somewhat arbitrary. AF persisting after 8 weeks despite straightforward dietary measures usually are designed as chronic [13]. However, there are morphological signs of chronicity (sentinel skin tag, hypertrophic papillae, indurated wound edged) that do not typically form in just a short period of an acute AF. Typical fissures occur in the midline, the majority of which are in the posterior midline of the anal canal. A chronic idiopathic AF can be clearly recognized as a well-circumscribed ulcer. Classical symptoms are pain on or after defecation that is often severe and may last from minutes to several hours. The patient may report that constipation is the antecedent event and, once pain has developed, fear of the act of defecation may

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Brisinda, Bianco, Silvestrini & Maria

exacerbate the problem. However, a history of antecedent constipation is obtained in only 25% of cases and diarrhea is noted as a predisposing factor in about 6% of patients [14–16]. AF can be seen as the buttocks are parted, and it is often suspected because there is marked spasm of the anus, making examination difficult. Digital or endoscopic examination is often impossible because of pain. Spasm of the IAS has been noted in association with AF [4,17]. Pathophysiology

The AF pathogenesis is poorly understood [18]. Surgical dogma states that a hard stool traumatizes the anal mucosa. Furthermore, the reasons for its failure to heal remain unclear. Also unexplained are the main characteristics of this painful condition, including the predilection for the posterior midline position and the lack of granulation tissue at the AF site [19]. Several theories have been advanced to unravel the underlying cause of AF [2,20]. Albeit the cause of the spasm remains obscure, it has been consistently found that resting anal pressure is higher in patients than in controls, suggesting that high resting pressure may be related to IAS spasm. Recognized features common to most AF are a reduced vascular perfusion index at the site of the fissure, and the presence of ultra-slow pressure wave activity in the IAS. It is generally believed that small traumatic tears in the lining of the anal canal fail to heal as a result of a reduced blood supply and so produce AF [21,22]. It has been also found that the IAS of patients with AF is fibrotic, compared with that of controls [23]; it was postulated that myositis might occur early in the course of the disease and that this was the underlying cause of both spasm and fibrosis [23,24]. It has been postulated that the increased AF incidence in the anterior and posterior midline positions is related to the distribution of vessels supplying blood to the anal canal [13,24–26]. Relief of symptoms and healing induced by treatment might be attributed to a decrease in anal pressure, allowing an increase in mucosal blood flow and relief of ischemia. Post-mortem angiography of the inferior rectal artery has revealed a paucity of inferior rectal artery branches at the posterior commissure in 35 of 41 subjects [27]. A morphological study of the capillaries revealed a reduced density in the sub-dermal space and within the IAS in the posterior midline in most specimens. Blood flow to the distal anal canal, measured by laser Doppler flowmetry, is inversely proportional to resting anal pressure. The AF predilection for the posterior midline and the lack of granulation tissue seen in the base of AF may therefore be explained by ischemia [22]. Decreased dermal blood flow may be promoted by endothelial cell dysfunction associated with reduced nitric oxide (NO) synthesis, which is known to be involved in the regulation of local blood flow. Interruption of endothelial continuity not only removes the anticoagulant and vasodilatory functions of the endothelium, but also exposes the subendothelium, which promotes several procoagulant functions. In addition, even in 512

the absence of detectable microscopic changes, endothelial function can change from vasodilatory to vasoconstricting, and from anticoagulant to procoagulant; these changes may be induced by inflammatory or immune cytokines. Activation of the endothelium may cause the expression of antigens; endothelial cells can act as antigen-presenting cells. Antiendothelial cell antibodies have been found in many patients with AF but not in healthy controls [2]. In antibody-positive patients, higher resting anal tone has been observed. The finding of circulating antiendothelial cell antibodies suggests that the lesion is primarily endothelial rather than at the IAS level. This supports a role for the endothelium in the pathogenesis of local ischemia. Circulating antibodies may activate the endothelium to produce vasoactive autacoids, which could contribute to the increased basal tone and aggravate the ischemia at the level of the posterior anal commissure. The observation that the topical application of glyceryl trinitrate (GTN) may induce healing of AF in up to 60% of cases supports a pathogenic role for endothelial NO synthesis [28]. A primary IAS disturbance (supersensitivity to b2 agonists) may be a contributory etiological factor. This may be induced by a prolonged absence of the neurotransmitter, by abnormalities at neurotransmitter or metabolic level or by a modification of cholinergic and adrenergic receptors. BT efficacy in inducing AF healing and reduction of resting tone suggests that increased IAS adrenergic or cholinergic activity is likely to occur in AF patients [29]. Treatment

Spasm of the IAS has been noted in association with chronic AF, and for many years treatment has focused on alleviating IAS hypertonia and lowering resting anal pressure [30,31]. AF shows great reluctance to heal without intervention. As the passage of a hard stool is thought to contribute to the AF development, the control of constipation has been considered the main treatment for years. Patients with a history that suggests only recent AF development are often successfully treated by conservative measures, such as stool softeners, bulking agents and a high-fiber diet [32,33]. To prevent recurrence, patients should be encouraged to continue with the diet, and to use laxative agent, if required, even after symptoms are resolved. However, this medical treatment is effective in patients with acute AF, while chronic AF requires surgical or pharmacological intervention [15,34,35]. Surgery

The most common treatment for AF has been lateral internal sphincterotomy, as described by Eisenhammer. The procedure remains the gold standard for AF treatment [36]. Although Eisenhammer’s technique is simple and effective, the fundamental drawback of this operation is its potential to cause minor, but often permanent, alterations in the control of gas, mucus and, occasionally, stool [37,38]. Nyam and Pemberton showed that lateral internal sphincterotomy healed and relieved symptoms in 96% of cases, while incontinence occurred frequently [39–44]. Traditional surgery Expert Rev. Pharmacoecon. Outcomes Res. 14(4), (2014)

Cost considerations in the treatment of AFs

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Table 1. Results of surgical treatment of patients with chronic anal fissure. Study (year)

Patients (n)

Technique open/close

Cure (%)

Recurrence (%)

Overall incontinence (%)

Ref.

Walker et al. (1985)

100

75/25

100

0

15

[85]

Lewis et al. (1988)

350

103/247

95.3

6

6.6

[86]

Khubchandani and Reed (1989)

1102

754/348

97.7

NR

NR

[44]

Pernikoff et al. (1994)

500

290/210

96

3

8

[87]

Usatoff and Polglase (1995)

98

98/0

68

30

18

[43]

Garcia-Aguilar et al. (1996)

549

324/225

89.1

10.9

41.3

[41]

Nyam and Pemberton (1999)

487

463/24

97.3

2.70

11.5

[39]

Libertiny et al. (2002)

35

NR

100

0

3

[88]

Parellada (2004)

27

27/0

100

0

15

[89]

Tocchi et al. (2004)

164

164/0

100

0

3

[90]

Casillas et al. (2005)

298

291/7

90

5.6

30

[42]

Rotholtz et al. (2005)

68

0/68

97

0

10.2

[40]

Arroyo et al. (2004)

40

40/0

92.5

2.5

5

[91]

Brown et al. (2007)

24

0/24

100

0

45

[92]

Renzi et al. (2008)

25

25/0

92

8

16

[93]

Algaithy (2008)

50

0/50

100

0

2

[94]

Abd Elhady et al. (2009)

40

40/0

90

10

0

[95]

Hancke et al. (2010)

21

21/0

100

0

47.6

[96]

Sileri et al. (2010)

72

72/0

98

2

0

[97]

Kement et al. (2011)

253

253/0

NR

NR

11.1

[5]

NR: Not reported.

permanently weakens the IAS, and incontinence after internal sphincterotomy is not insignificant (TABLE 1). A recent systematic review and meta-analysis has shown that overall continence disturbance rate after internal sphincterotomy was 14% [35]. Weighted analysis showed flatus incontinence in 9%, soilage/ seepage in 6%, accidental defecation in 0.9%, incontinence to liquid stool in 0.6% and incontinence to solid stool in 0.8% of patients. Whether an open or closed technique is used does not seem to influence incontinence rates [35]. Caution must be exercised when contemplating internal sphincterotomy, particularly in elderly patients or those with diarrhea, irritable bowel syndrome, diabetes or recurrent fissure after previous surgery [38]. Anal dilatation is a non-standardized uncontrolled procedure, which disrupts and may lead to permanent damage of the sphincter mechanism. Healing rate of 40–70% has been reported with this technique, and recurrence rates of up to 56% [45,46]. Of greater concern are reports of incontinence to flatus and soiling in 39%, and fecal incontinence in 16%. A recent study has shown that lateral internal sphincterotomy is superior to anal dilatation in terms of healing, and poses less of a threat to continence [47]. informahealthcare.com

Chemical sphincterotomy

More recently, various pharmacological agents have been shown to lower anal pressure and heal fissures. This so-called ‘chemical sphincterotomy’ has become accepted first-line treatment for chronic AF in many centers. Furthermore, with the ready availability of medical therapy, the risk of a first-line surgical approach is difficult to justify. The surgical approach to AF is reserved for patients who have tried medical treatment for at least 1–3 months, but have failed. NO donors

NO donors may promote the AF healing by increasing local blood flow in two ways: by reducing intra-anal pressure and by having a vasodilatory effect on the anal vessels [48]. GTN and isosorbide dinitrate are metabolized at a cellular level to release NO and have been shown to heal chronic AF. The dose of GTN has not been standardized and depends on the concentration and the volume of ointment applied [49]. Benefit from GTN is not always permanent. It has recently been reported that treatment with topical GTN is less efficacious than previously thought. A regimen using a pea-sized amount of 0.2% 513


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GTN ointment (~0.5 g) applied two- or three-times daily to the distal anal canal for 8 weeks, has been shown to heal two-thirds of chronic AF. Lund and Scholefield used 0.2% GTN ointment and showed that it decreased resting anal pressure by 33% and induced an increase in anodermal blood flow [50]. Furthermore, ointment significantly reduces pain within 5 min of application. Studies have shown a healing rate of 33–68% [51–54]. Between 19 and 58% of patients experience transient headache when using topical GTN preparations and many have reported a burning sensation in the anus [11,49]. One study highlighted issues relating to poor patient compliance: in 62% of these patients side effects of the treatment have been interfered with their quality of life [55]. Moreover, high doses of GTN are not more efficacious in inducing healing [56]. An important issue is the development of drug tolerance, which is well documented when the same drugs are used to treat cardiovascular diseases. Nitrates have a short duration of action and so frequent application is necessary; side effects, such as headaches and tachyphylaxis, further limit their usefulness. Interestingly, there is no correlation between plasma GTN concentration, resting anal pressure and the onset, duration or intensity of headache. Recent studies suggest that GTN is labor intensive for patients and that its results are not superior to those of lateral internal sphincterotomy [37,52]. Alternative nitrates, such as isosorbide dinitrate, have been investigated. This agent (1 g 1% ointment applied every 3 h throughout the day) achieved healing in 30 of 34 patients. Similarly, healing was demonstrated in 34 of 41 patients following its topical use in a dose of 1.25 or 2.5 mg applied three-times daily [57–60]. Calcium channel antagonists

Diltiazem and nifedipine are widely prescribed in clinical practice as antianginal and antihypertensive agents [48,55,61]. They act by blocking slow L-type calcium channels in vascular smooth muscle, and recently have also been shown to lower resting anal pressure presumably by a similar action on the IAS smooth muscle. Calcium channel antagonists (CCA) decrease IAS tone if given sublingually or orally. In the first clinical study, 20 mg sublingual nifedipine caused (at 30 min) a 32 and 24% reduction in anal canal pressure, respectively, in AF patients and normal volunteers, without any significant effect on blood pressure or heart rate [62]. An oral dose of 20 mg twice daily produced a 36% fall in mean anal resting pressure, and healing was achieved by 8 weeks in 9 of the 15 treated patients [63]. Topical diltiazem (2 cm of 2% gel squeezed from the tube, or ~0.7 g) has been shown to heal 65–75% of chronic AF. In a study, patients were treated with 2% diltiazem gel three-times daily for 8 weeks and AF healed in 67% of patients [64]. There was a significant decrease in pain score after treatment with diltiazem (p = 0.002); resting anal pressure was significantly lowered (p = 0.0001) than baseline value. No headache or other side effects were reported [64]. Jonas et al. assessed the efficacy of oral and topical diltiazem in healing chronic AF. AF healing 514

was 38% in the oral group and 65% in the topical group after 8 weeks [65]. Knight et al. studied the effect of 2% topical diltiazem in 71 patients. Healing was observed in 88% of the patients, after 5 months of treatment [66]. DasGupta et al. found that AF healed in 48% of patients treated with diltiazem gel, including 75% of the patients who previously failed to heal with GTN ointment [67]. Kocher et al. performed a randomized controlled trial assessing the side effects of GTN and diltiazem in the treatment of chronic AF. More headaches occurred with GTN than with diltiazem (p = 0.01) [68]. There was no significant difference in healing and symptomatic improvement rates between the two groups. A recent systematic review supports the superiority of diltiazem over GTN for chronic AF [48]. However, the study has limitation, and the long-term results may show a variable degree of efficacy and recurrence. We believe that a multicenter, randomized controlled trial is required to validate these findings and to evaluate secondary outcome variables, such as cost–effectiveness and measurement of health-related quality of life. Botulinum toxin

BT can be used to treat AF (TABLE 2). The IAS was palpated and injected with a 27-gauge needle while the patient was lying on his or her left side. In a double-blind study, a success rate of 76% was achieved following a single treatment with 20 units [8]. A prospective comparison between two dose regimens (15 and 20 units) showed negligible side effects and no complications; symptomatic improvement was achieved in both groups of patients, but the healing rate was higher in the group receiving 20 units [7]. It has been also demonstrated that AF healing is induced more efficiently by BT treatment than by GTN, and that IAS hypertonia is also alleviated more effectively [6,69]. The therapeutic efficacy of different BT doses in AF has been reported recently; the rate of healing did not differ significantly when the total dose and the number of injection sites were varied [70]. In our experience, patients with a posterior AF have better results when BT is injected anteriorly into the IAS [71]. Anteriorly placed injections induce a higher fall in resting pressure and improve clinical outcome. Fibrosis of the IAS, which is more prominent at the AF site than elsewhere in the smooth muscle [23], may reduce IAS compliance and limit the diffusion of toxin. Moreover, a chronic reduction of perfusion in the posterior part of the anus may affect the myenteric nerve fibers at this location and make them less sensitive to the BT action [72]. To compare the efficacy and tolerability of two different formulations of type A BT, and to provide more evidence with regard to the choice of dosage regimens, symptomatic adults with chronic AF were enrolled in a randomized study [73]. Fifty patients received injections of 50 units of Botox formulation (group I), and 50 patients received injections of 150 units of Dysport toxin (group II), assuming that with a conversion factor between their potency of 3, the efficacy and tolerability of the two formulations are the same. One month after Expert Rev. Pharmacoecon. Outcomes Res. 14(4), (2014)


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Table 2. Results of treatment with botulinum toxin. Study (year)

Patients (n)

Units/injection site

Complete healing rate (%)

Temporary incontinence (%)

Recurrence (%)

Complications (%)

Ref.

Gui et al. (1994)

10

15 B/IAS

90

10

10

10

[98]

Jost and Schimrigk (1993)

12

5 B/EAS

83.3

0

8.3

0

[99]

Jost and Schimrigk (1995)

54

5 B/EAS

78

6

6

11

[100]

Jost (1997)

100

2.5–5 B/EAS

82

7

8

0

[101]

Maria et al. (1998)

15

20 B/IAS

100

4

6.7

0

[8]

Maria et al. (1998)

23 34

15 B/IAS 20 B/IAS

100 100

0

0

0

[7]

Minguez et al. (1999)

23 27 19

10 B/IAS 15 B/IAS 21 B/IAS

83 78 90

0

37–52

0

[70]

Jost (1999)

25 25

20 D/EAS 40 D/EAS

76 80

4 12

4 8

0

[102]

Brisinda et al. (1999)

25 25

20 B/IAS 0.2% GTN

96 60

0

0

0

[6]

Fernandez et al. (1999)

76

40 B/IAS

67

3

0

1

[103]

Madalinski et al. (1999)

13

20 B/EAS

–

NR

15.4

NR

[104]

Maria et al. (2000)

25 25

20 B/IAS PI 20 B/IAS AI

80 100

0

0

0

[71]

Lysy et al. (2001)

15 15

20 B+ID/IAS 20 B/IAS

73 60

0

0

0

[105]

Madalinski et al. (2001)

14

25–50 B/EAS

54

0

8

0

[106]

Tilney et al. (2001)

10

NR D/IAS

NR

NR

20

[107]


75 75

20 B/IAS 30 B/IAS

100 100

0 3

0 4

0

[74]


6

150 D/IAS

100

0

0

0

[108]

Mentes et al. (2003)

61 50

20–30 B/IAS LIS

86.9 98

0 16

11.4 0

0

[109]

Siproudhis et al. (2003)

22 22

100 D/IAS Saline

NR

NR

NR

22.7 22.7

[110]


50 50

50 B/IAS 150 D/IAS

92 94

22 16

0

0

[73]

Giral et al. (2004)

10 11

20 B/IAS LIS

70 82

0

0

0

[111]

Simms et al. (2004)

47

30 B/IAS

78.7

NR

27

0

[112]

Lindsey et al. (2004)

30

25 B/IAS + F

93

7

0

0

[113]


40 40

25 B/IAS LIS

45 92.5

5 2,5

5.5 7.5

2.5 10

[114]


100

25 B/IAS

47

6

53

0

[115]

AI: Injection in anterior midline; B: Botox (trade name of the type A preparation manufactured by Allergan, Irvine, CA, USA); D: Dysport (trade name of the type A preparation manufactured by IPSEN, Maidenhead, UK); DZ: Diltiazem; EAS: External anal sphincter; F: Fissurectomy; GTN: Glyceryl trinitrate; IAS: Internal anal sphincter; ID: Isosorbide dinitrate; LIS: Lateral internal sphincterotomy; MC: Mucocutanous; NR: Not reported; PI: Injection in posterior midline; Pinj: Placebo injection; Poin: Placebo ointment.

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Table 2. Results of treatment with botulinum toxin (cont.). Study (year)

Patients (n)

Units/injection site

Complete healing rate (%)

Temporary incontinence (%)

Recurrence (%)

Complications (%)

Ref.


50 50

30B-90D/IAS 0.2% GTN

92 70

0 0

0 7

6 34

[69]


80

30B-90D/IAS

74

10

0

0

[75]

De Nardi et al. (2006)

15 15

20 B/IAS 0.2% GTN

33.3 40

0

33 33

0

[116]

Scholz et al. (2007)

40

10 B/IAS + F

79

2.5

10

0

[117]

Aivaz et al. (2009)

40 19

LIS 80 B/IAS + F

90 74

NR

0 5

10 0

[118]

Festen et al. (2009)

37 36

20 B/IAS + Poin 1% ISDN + Pinj

37,8 58,3

NR

13,5 25

0

[57]

Nasr et al. (2010)

40 40

20 B/IAS LIS

62,5 90

0 10

40 12,5

0 5

[31]

Samim et al. (2012)

60 74

20 B/IAS 2% DZ

43.3 43.2

NR

11.7 17.6

NR

[119]

Valizadeh et al. (2012)

25 25

50 B/IAS LIS

48 92

12 44

50 8

0 4

[120]

AI: Injection in anterior midline; B: Botox (trade name of the type A preparation manufactured by Allergan, Irvine, CA, USA); D: Dysport (trade name of the type A preparation manufactured by IPSEN, Maidenhead, UK); DZ: Diltiazem; EAS: External anal sphincter; F: Fissurectomy; GTN: Glyceryl trinitrate; IAS: Internal anal sphincter; ID: Isosorbide dinitrate; LIS: Lateral internal sphincterotomy; MC: Mucocutanous; NR: Not reported; PI: Injection in posterior midline; Pinj: Placebo injection; Poin: Placebo ointment.

injection, 11 patients in group I and 8 patients in group II had mild incontinence of flatus. At the 2-month evaluation point, 46 patients in group I and 47 patients in group II had a healing scar. In group I patients, the mean resting anal pressure was 41.8% lower, and the maximum voluntary squeeze pressure was 20.2% lower, than the baseline value. In group II patients, the resting anal pressure and maximum voluntary squeeze pressure were 60.0 ± 12.0 and 71.0 ± 30.0 mmHg, respectively. There were no relapses during an average of about 21 months of follow-up [73]. In a recent study, the influence of two different dosage regimens injected anteriorly in the IAS on the clinical outcome of patients with a posterior AF was investigated [74]. Healing of the fissure and symptomatic improvement were achieved in both groups of patients. Two months after injection, 89% treated with 20 units and 96% treated with 30 units had a healing scar; three patients in the latter group had a persistent AF in the absence of symptoms. These results suggest that higher doses led to a higher success rate. Resting anal pressures were significantly lower than pretreatment values in both groups; although maximum voluntary pressure was unchanged in patients treated with 20 units, it was significantly lower than the pretreatment value in patients treated with 30 units, probably related to a diffusion of toxin to the external anal sphincter (EAS). BT diffusion in the tissues is a dose-dependent phenomenon. It has been observed that BT injections into the EAS are also effective for treating AF. The mechanism is probably mediated by diffusion to the IAS. However, since the 516

fundamental pathogenic event in AF is IAS spasm, injection into the EAS cannot be the first choice of treatment. In addition, the IAS is easier to inject than the EAS. Cost-saving effect of treatment algorithm

The risk of permanent incontinence after surgery has stimulated a number of lines of research seeking medical therapies that allow chemical sphincterotomy. Hence, conservative AF treatment was not only a therapeutic tool, but also a diagnostic test to identify those patients not suitable for a sphincterotomy [75]. Chemical sphincterotomy should be used as first-line tool in patients who suffer from chronic AF, more than ever in presence of risk factors for incontinence. It leads to fissure healing in more than 60–70% of cases, decreasing the number of unsafe and expensive lateral internal sphincterotomy [69,75]. Furthermore, it yields the socioeconomic advantages of a rapid solution of the condition, which does not require admission to hospital, preoperative studies and operating theatre. The addition of chemical sphincterotomy to the armamentarium for the management of primary and recurrent AF should be considered an improvement. Recently, Sierra, who aimed to consider negative and positive aspects induced by any medical or surgical approach, performs a statistical analysis, based on evidence-based medicine principles, to choose between BT injection and lateral internal sphincterotomy, the best treatment for AF [76]. Considering the number of patients that benefit from the sphincterotomy versus every patient harmed by the operation, in comparison with BT Expert Rev. Pharmacoecon. Outcomes Res. 14(4), (2014)



treatment, the author obtains a result in favor of BT treatment. Moreover, evaluation of the actual costs of each therapeutic option is dramatically important, especially in times of economic crisis and downsizing of health spending. A manuscript on the cost-saving effect of a treatment algorithm including topical nitroglycerin, type A BT and lateral internal sphincterotomy to manage chronic AF has been published by Essani and coworkers [77]. Aimed to demonstrate the effectiveness and cheapness of this stepwise escalation, that use, to treat AF, first topical nitroglycerin then, in case of failure at 4 weeks followup, injection of 40 IU of BT, and finally, after 4 weeks, in non-responders to the medical approach, surgical sphincterotomy, the authors perform a cost analysis by calculating the effective and hypothetical total cost of the algorithm and of two alternative models. The first, called Brisinda approach, is based on the use of BT injection in all cases, leaving surgery for the toxin’s failures; besides, the second approach, named Nelson approach, is based on the exclusive use of lateral internal sphincterotomy to cure all patients. The statistical examination is based on a prospective trial of 67 AF patients symptomatic for longer than 3 months treated using the multistep approach. Nitroglycerin application was successful in 46.2% of the patients; three patients then required surgery; subsequently, BT was effective in 28 of 33 patients (84.8%), while the overall surgery rate was 11.9% [77]. Based on the above-mentioned rates, considering that the purchase cost for nitroglycerin ointment is US$10 and that of a BT vial is US$528, while the procedure cost is US$1119 for surgery and US$148 for toxin injection, the total cost for these 67 patients was US$33,282, including US$290 for nitroglycerin treatment, US$20,580 for nitroglycerin plus BT and finally US $9025 for nitroglycerin ointment plus BT plus lateral internal sphincterotomy, considering that a BT vial is used for every patient. Furthermore, based on the same healing rate, the authors underline that using the Brisinda approach (injection for 67 patients and toxin plus surgery in non-responders that are 15.2% of cases), the total cost rises to US$56,688; that means a 70.3% increase comparing with the algorithm approach. On the contrary, this calculation is performed assuming that a BT vial containing 100 units is used for every patient, thus a cost of US$45,292 for BT treatment. If we consider the price of 40 IU of BT used for every patient, according to the protocol, the BT cost treatment decreases to US$24,066, so the total cost of the Brisinda strategy decreases to US$45,292; that means an increase of 36% compared with the multistep approach [78]. Besides, the therapeutic effects of different doses of BT in AF have been recently reported in literature. According to these results, we do not believe that higher doses (50 or 100 units) are necessary, as we are able to produce an adequate effect using 20–30 units of Botox formulation or 60–90 units of Dysport formulation [73]. With increasing BT doses, the degree of denervation at the injection site increases, improving the rate of side effects and the cost of treatment [74]. In previous studies, after the injection of 20 units posteriorly, the mean resting pressure, with respect to the baseline informahealthcare.com

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value, was 23–27% lower at the 1-month evaluation and 22–28% lower at the 2-month evaluation, whereas the maximum voluntary squeeze pressure was not changed significantly. Furthermore, in recent studies, we have shown that, by choosing a different injection site (anterior IAS aspect) and by using a higher dose (30 Botox units), a greater decrease can be induced in both the resting anal pressure and maximum voluntary contraction [69]. If we calculate the cost of the Brisinda approach model using 20 or 30 units of Botox formulation, we will obtain a relevant decrease of a total cost to US$29,300 and US$32,837, respectively. In addition, with the use of Dysport formulation, the model becomes even more cost saving, considering that a Dysport vial contains 500 units that are enough to treat eight or five patients with 60 or 90 IU, respectively [78]. Furthermore, performing one or, if necessary, more rescue BT treatments instead of surgery, according to our clinical experience, it is possible to reduce the cost of the therapy cutting the high cost of surgery in nearly all patients. Moreover, as mentioned above in our clinical trials, we constantly observed an increase of healing rate of patients treated with BT between 1 and 2 months follow-up. Thus, it is possible to reduce the overall cost of the BT treatment performing the rescue treatment 2 months after the last injection instead of at 4 weeks follow-up as Essani performed. The total cost for the surgery treatment of all 67 patients, according to Nelson strategy, was US$74,973; that means a 125.3% increase compared with the multistep approach. Although considerable, this calculation left out additional costs that might result from perioperative time off work, surgical fees and surgical complications like bleeding, infection and especially fecal incontinence [38,79]. Fecal incontinence may appear after surgery and lead to permanent disturbance of life [17,39]. We believe that anal incontinence after lateral internal sphincterotomy should be considered as a failure of the surgical treatment [80]. What is the cost of the treatment of a case of fecal incontinence? We have calculated the costs of possible therapeutic approaches. We have identified a hypothetical population consisting of 100 AF patients. The accounts have been made out of a population of 100 patients in order to make easier the calculation of percentages. Regarding the healing rate, we have made reference to the experiences of literature. Cost analysis was based on the direct costs for ointments, BT injection and surgery as well as on the assumption that the number of follow-up visits would be equal in all patients regardless of the treatment. We used the prices of individual treatments as reported in the previous paragraph. We have not taken into account the cost of the complications of each treatment approach. We have only considered the costs of AF healing. Therapeutic approaches identified are three. The first approach is exclusively surgical, based on the evidence that surgery is the gold standard, and all patients should undergo surgery as the only treatment. The second approach is referred to as the ointment-based, and in this context have been identified two orientations depending on the use of GTN ointment (FIGURE 1) or 517

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100 AF patients €21.927,00

Healing rate 65%

35 patients not healed

Botulinum toxin €1.651,51 Botox €1.229,93 Xeomin €1.336,51 Dysport

Surgery €42.078,05

Total cost €49.752,50 (surgery €42.078,05 plus GTN ointment €7.674,45)

Total cost (toxin injection plus ointment) €9.325,96 Botox €9.010,96 Dysport €8.904,38 Xeomin

31 patients healed


Surgery €4.808,92

Total cost (ointment plus toxin plus surgery) €5.874,74 Botox €5.838,74 Dysport €5.826,56 Xeomin

Figure 1. Economic evaluation in glyceryl trinitrate-based treatment. AF: Anal fissures; GTN: Glyceryl trinitrate.

nifedipine ointment (FIGURE 2). The third approach is based on the use of type A BT (FIGURE 3). Procedural costs, based on reimbursement rates, was e1.202,23 for lateral internal sphincterotomy, which includes the surgeon’s fee as well as the hospital cost for the procedure, in day surgery setting. The anal dilators exist in two packages; the first (Dilatan, pack with three dilators) has a cost of e40.26, while the second (Dilatan plus, pack with two dilators) has a cost of e26.84. Commercial preparations available in Italy and treatment costs for each patient are shown below. The prices of the drugs were determined by the Price Commission of the Ministry of Health. GTN ointment has the commercial name of Rectogesic and is marketed in Italy by Prostraskan Ltd. One gram of rectal ointment contains 40 mg of GTN in propylene glycol corresponding to 4 mg of GTN. In 375 mg of this formulation 518

approximately 1.5 mg of GTN is present. A pack of 30 g ointment has a price of e73.09. The treatment proposed is based on the application of 0.5 g of ointment three-times a day for 8 weeks. Each patient is required to complete treatment of three packs of ointment for a total cost of e219.27. Nifedipine ointment has the trade name Antrolin and is marketed in Italy by New.Fa.Dem. Srl in packs of 30 g at a concentration of 0.3%. A pack of 30 g ointment has a price of e12.90. The treatment proposed is based on the application of 0.7 g of ointment three-times a day for 8 weeks. Each patient needs four packages of cream to complete the treatment. The total cost will be e51.6. Diltiazem gel was excluded from the analysis because it is not marketed in Italy. Currently, three formulations of type A BT are available in Italy. With regard to the toxin present in the Italian market, we have made reference to the ex-factory prices. The ex-factory Expert Rev. Pharmacoecon. Outcomes Res. 14(4), (2014)


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100 AF patients €5.160,00

Healing rate 70%


Botulinum toxin €1.415,58 Botox €1.145,58 Dysport €1.054,23 Xeomin

Surgery €36.066,90

Total cost €37.614,90 (surgery €36.066,90 plus nifedipine ointment €1.548,00)

Total cost (toxin injection plus ointment) €2.808,78 Botox €2.538,78 Dysport €2.447,43 Xeomin

27 patients healed


Surgery €3.606,69

Total cost (ointment plus toxin plus surgery) €3.903,04 Botox €3.876,04 Dysport €3.866,91 Xeomin

Figure 2. Economic evaluation in nifedipine-based treatment. AF: Anal fissures.

prices are determined by the Price Commission of the Ministry of Health as a result of a negotiation with the manufacturer. This price is the maximum price at which the drug can be sold to hospital pharmacies. At this price, 10% VAT must be added. The formulation of onabotulinumtoxin A is marketed in Italy in vials containing 100 IU under the trade name Botox and is manufactured by Allergan (Irvine, CA, USA). The cost of one vial of 100 IU is e157.28. The formulation of abobotulinumtoxin A is marketed in two vials containing 500 IU each with the trade name of Dysport, produced by Ipsen (Maidenhead, UK); the cost is e424.29. The third formulation, incobotulinumtoxin A, has the trade name Xeomin and is manufactured by Merz Pharma Italia Srl (Italy). Each vial contains 100 IU and costs e117.13. The proposed treatment is based on the injection of 30 IU of type A BT with a cost of e47.18 using Botox. Using the formulation Dysport and a conversion factor of 1:3, each patient will be treated with informahealthcare.com

90 IU of BT at a cost of e38.18. Using the formulation Xeomin, each patient will be treated with 30 IU BT, at a cost of e35.14. The first approach, surgical approach, has a total cost of e120.223. We think that a direct surgical approach is too expensive. In addition, we believe that surgical treatment is not justified as a treatment of first choice. Furthermore, the anal dilator was not taken into account, because we believe that it is not a valid treatment for AF patients. The GTN ointment approach has an initial cost of e21.927,00. Assuming a healing rate at 2 months of 65% of the patients, we have 35 patients who need further treatment. If these patients undergo surgical treatment, the cost will increase to e42.078,05, for a total expenditure of e49.752,5 (e42.078,05 added to e7.674,45 ointment in these 35 patients). If, however, the 35 patients are undergoing BT treatment, the costs would amount to e1.651,51 for Botox, 519

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100 AF patients €4.718,60 Botox €3.818,60 Dysport €3.514,10 Xeomin

Healing rate 85%


Ointment (€3.289,05 Rectogesic, €774,00 Antrolin)

Surgery €18.033,45

Total cost €18.741,24 Botox €18.606,24 Dysport €18.560,56 Xeomin

Total cost (toxin injection plus ointment) €3.996,84 for Rectogesic and Botox €1.481,79 for Antrolin and Botox €3.861,84 for Rectogesic and Dysport €1.346,79 for Antrolin and Dysport €3.816,16 for Rectogesic and Xeomin €1.301,11 for Antrolin and Xeomin

10 patients healed


Surgery €6.011,15

Total cost (ointment plus toxin plus surgery) €7.343,43 for Botox and Rectogesic €6.505,08 for Botox and Antrolin €7.298,43 for Dysport and Rectogesic €6.460,08 for Dysport and Antrolin €7.283,20 for Xeomin and Rectogesic €6.444,85 for Xeomin and Antrolin.

Figure 3. Economic evaluation in toxin-based treatment. AF: Anal fissures.

e1.229,93 for Xeomin and e1.336,51 for Dysport. The total expenditure in these 35 patients would therefore be e9.325,96 for Botox, e8.904,38 for Xeomin and e9.010,96 for Dysport. Assuming the healing only in 31 of them, 4 patients would undergo surgery at a cost of e4.808,92. In these four patients, the overall expense would be given by the sum of e877.08 for the ointment, e188,74 for Botox, e140,56 for Xeomin, e152,74 for Dysport, and e4.808,92 for the intervention, for a total of e5.874,74 for Botox, e5.826,56 for Xeomin and e5.838,74 for Dysport. The nifedipine ointment approach has an initial cost of e5.160,00. Assuming a healing rate at 2 months of 70% of the patients, we have 30 patients who need further treatment. If these patients undergo surgical treatment, the cost will increase to e36.066,90 for a total expenditure of e37.614,90 520

(e36.066,90 added to e1.548,00 ointment in these 30 patients). If, however, the 30 patients are undergoing BT treatment, the costs would amount to e1.415,58 for Botox, e1.054,23 for Xeomin and to e1.145,58 for Dysport. The total expenditure in these 35 patients would therefore be e2.808,78 for Botox, e2.447,43 for Xeomin and e2.538,78 for Dysport. Assuming the healing only in 27 of them, 3 patients would undergo surgery at a cost of e3.606,69. In these three patients, the overall expense would be given by the sum of e154.80 for the ointment, e141.55 for Botox, e105.42 for Xeomin, e114.55 for Dysport and e3.606,69 for the surgical procedure, for a total expense of e3.903,04 for Botox, e3.866,91 for Xeomin and e3.876,04 for Dysport. The BT approach has an initial cost of e4.718,60 for Botox, e3.818,60 for Dysport and e3.514,10 for Xeomin. Assuming Expert Rev. Pharmacoecon. Outcomes Res. 14(4), (2014)



a healing rate at 2 months of 85% of the patients, we have 15 patients for further treatment. If these patients undergo surgical treatment, the cost will increase to e18.033,45, for a total expenditure of e18.741,24 for Botox, e18.606,24 for Dysport and e18.560,56 for Xeomin (e18.033,45 added to e707.79 for Botox, e572.79 for Dysport and e527.11 for Xeomin in these 15 patients). If, however, the 15 patients are undergoing treatment with ointment, the costs would amount to e3.289,05 for Rectogesic and e774.00 for Antrolin. The total expenditure in these 15 patients has been reported in FIGURE 3. Assuming the healing only in 10 of them, 5 patients would undergo surgery at a cost of e6.011,15. Conclusion

This review is based on available up-to-date published works and reports. Chronic AF tends to be persistent or recurrent. It is a common problem that causes significant complications in a young and otherwise healthy population, with a roughly equal incidence in both sexes. Internal sphincterotomy remains a good operation for bringing rapid pain relief with a high degree of patient satisfaction [11,79]. However, concern remains about its lack of standardization, potentially exposing some patients to the risk of a permanent disturbance in anal continence. The results have neither been modified by use of modified techniques, such as tailored sphincterotomy, nor by selection of patients. Thus according to many authors, we recommend a safety first approach and treat all patients medically in the first instance [11,35]. We believe that specific indications for surgical intervention in AF patients include persistence/ recurrence, non-compliance or intolerance to the medical treatment. Patients at higher incontinence risk can be evaluated by anorectal manometric and endoanal sonography test, or, at best, the patient should be offered a sphincter-sparing procedure [11,35]. The need for further investigations imposes a cost increase. Furthermore, it is difficult to calculate the increased cost in the event of complications. Some of these patients may wish to avoid internal sphincterotomy and persist with an alternative medical therapy. The recommendations are that simple and readily available therapy associated with fewer complications and requiring no hospitalization should be offered as first line for AF care. Rational thinking suggests conservative measures as the first-line therapy given that they are simple and have good safety records. NO donors are readily available and many reports support these agents as the starting point in the AF management. Nevertheless, drawbacks of these drugs are headaches, orthostatic hypotension and tachyphylaxis [29], which usually limit their benefits and call for second-line therapy, such as CCA or BT. BT injection has an excellent healing rate, can be repeated if necessary, and obviates the patients’ compliance. However, BT potential side effects should be kept in mind, including patient aversion to injection. Recently, Mishra et al. concluded that both treatments (NO donors and BT) may be considered as first-line treatment even if less effective than surgery [81]. However, this view has been informahealthcare.com

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challenged by other observations based on smaller series, providing inferior evidence of efficacy. The results of some studies are so disappointing that it led Nelson and coworkers to conclude a Cochrane review stating that ‘medical therapy for chronic AF may be applied with a chance of cure that is only marginally better than placebo’ [82]. We think that such conclusion is too pessimistic, and welcome further multicenter trials with appropriate methodology (intention-to-treat-based selection of patients, doses and injection technique) and adequate follow-up, to ascertain the safety and efficacy of the therapy. Moreover, the addition of multiple treatment modalities prolonged time to healing from initial evaluation, but allowed up to 75% of patients to avoid the need for permanent sphincter division while maintaining the highest rate of healing. We believe that the introduction of conservative therapies, and especially of BT, in the treatment of AF patients represents an innovation equal to the introduction of laparoscopy. The introduction of these therapies has made the AF treatment easier, in the outpatient setting, at a lower cost and without permanent complications. On the other hand, laparoscopy has led to an increase in the cost of a single surgical procedure, often with a higher incidence of complications than open surgery. With regard to AF, any conservative treatment used has lower costs than surgery. Considering the three hypothetical scenarios previously reported, we found that the BT approach is more cost-effective than the ointment approach. In addition to cost reduction (on average 62% lower than the association NO donors plus surgery and on average 50% lower than the association CCA plus surgery), BT reduces the number of patients who need further surgery. Moreover, we have found that the preparation of incobotulinumtoxin A has a lower price than preparations onabotulinumtoxin A and abobotulinumtoxin A. This figure, given the similar clinical efficacy of the three formulations, would lead us to prefer the incobotulinumtoxin A. It must be stressed, however, that the prices of the three formulations are not very dissimilar. Expert commentary

Conservative AF therapies have an excellent safety and tolerability profile. Reported adverse effects are temporary, mild-tomoderate in intensity, local and related to the mechanism of action. BT is a safe treatment for AF patients. It is less expensive and easier to perform than surgical treatment and does not require anesthesia [69,75]. It is also more efficacious than nitrate therapy and is not related to the patients’ willingness to complete treatment [6,69]. We believe that BT treatment should be considered the first-line therapy in patients with chronic AF. Five-year view

AF treatment has been directed to relax increased sphincter tone. Surgery has been considered the gold standard approach with healing rate of approaching 95% [83]. However, concerns have been raised about AF persistence or recurrence, reported in literature in up to 10% of patients [17,38,84]. Furthermore, 521


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postoperative impairment of fecal incontinence and persistence of fissure after surgery are not uncommon [35,40]. Hence, the significant incidence of fecal incontinence remains the ‘Achilles Heel’ of sphincterotomy. The risk of permanent incontinence after surgery has stimulated a number of lines of research seeking medical therapies that allow chemical sphincterotomy. Performing one or, it necessary, more conservative treatments instead of surgery, it is possible to reduce the cost of the therapy, cutting the high cost of surgery in nearly all patients. BT injection should be used as first-line tool in patients who suffer from chronic AF, more than ever in presence of risk factors for incontinence. It leads to fissure healing in more than 75% of cases decreasing the number of unsafe and expensive

surgery [69,75]. Furthermore, it yields the socioeconomic advantages of a rapid solution of the condition. Considering the three hypothetical scenarios previously reported, we found that the BT approach is more cost-effective than the ointment approach. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Chronic anal fissure (AF) is a cut or crack in the anal canal or anal verge. Chronicity is defined by both chronology and morphology. • AF causes and the reasons for their failure to heal remain unclear. • Recognized features common to most chronic AF are a high resting anal pressure owing to internal anal sphincter (IAS) hypertonicity. • Lateral internal sphincterotomy is a surgical technique to cure AF. It has been favored by most of the surgeons, because it offers long-lasting relief in sphincter spasm. • Surgery permanently weakens the IAS and may lead to anal incontinence. Although most episodes of incontinence are minor and transient, in a subset of patients incontinence is permanent. • Nitric oxide donors may promote healing of anal fissure by increasing local blood flow. Many patients have experienced transient headache when using topical glyceryl trinitrate (GTN) preparations and have reported a burning sensation in the anus. • Benefit from GTN is not always permanent, and recently, it has been stated that the treatment with topical GTN is less efficacious than previously reported. • It may, therefore, be possible to lower anal sphincter pressure using calcium channel antagonists and cholinergic agonists without side effects. Nifedipine has also been used in treatment of chronic AF as reported in a number of studies. A combination of lidocaine and nifedipine can be a reliable non-surgical method for treating AF. • Botulinum toxin (BT) is widely commercially available. Three preparations are available for clinical use. • BT appears as a safe treatment for patients with chronic AF. It is easier to perform than surgical treatment and does not require anesthesia. It is also more efficacious than nitrate therapy. No adverse effects or permanent IAS damage have resulted from BT injection. • BT injection has an excellent healing rate, can be repeated if necessary and obviates the patient’s compliance. The potential BT side effects should be kept in mind, however, including patient aversion to injection. One major problem of conservative therapy for AF is compliance. • BT therapeutic approach is more cost-effective than the ointment approach.

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Increasing efficacy and reducing side effects in treatment of chronic anal fissures: A study of topical diazepam therapy.

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The cost of fetal research: ethical considerations.

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Basic considerations in the treatment of obesity.