ORIGINAL ARTICLE
Comparison of intranasal fluticasone spray, budesonide atomizer, and budesonide respules in patients with chronic rhinosinusitis with polyposis aer endoscopic sinus surgery Paul D. Neubauer, MD1 , Zachary G. Schwam, BA2 and R. Peter Manes, MD, FACS1
Background: Nasal steroids are a critical part of the management of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) aer endoscopic sinus surgery (ESS). Increasingly, practitioners are using budesonide respules delivered to the sinonasal cavities, which is an off-label use, in lieu of traditional nasal steroids. There has been little research comparing budesonide with traditional nasal steroids and the most effective delivery method of budesonide. Methods: A randomized controlled trial was performed on patients aer ESS for CRSwNP in a tertiary care center. Patients were randomized into 1 of 3 groups: group A received fluticasone nasal spray twice daily; group B received budesonide respules via a mucosal atomization device (MAD) twice daily; and group C received budesonide respules instilled via the vertex-to-floor (VF) position twice daily. Primary endpoints were 22-item Sino-Nasal Outcome Test (SNOT-22) and Lund-Kennedy scores at 6 months. Results: Thirty-two patients were enrolled in the study, 23 of whom completed the 6-month trial. There were no significant differences among groups A, B, and C with respect to age, gender, asthma, aspirin
sensitivity, or previous ESS. Group B had a statistically significant greater reduction in SNOT-22 and Lund-Kennedy scores at the primary endpoint of 6 months compared to groups A and C. Group C had the next greatest reduction, which was statistically significant, followed by group A. Conclusion: Patients treated with budesonide aer ESS for CRSwNP had greater improvement in SNOT-22 and LundKennedy scores compared to fluticasone at 6 months. The data supports the use of budesonide respules, particularly with a MAD, over fluticasone for CRSwNP patients aer C 2015 ARS-AAOA, LLC. ESS.
Key Words: chronic disease; sinusitis; administration topical drug; offlabel use; surgical procedure endoscopic How to Cite this Article: Neubauer PD, Schwam ZG, Manes RP. Comparison of intranasal fluticasone spray, budesonide atomizer, and budesonide respules in patients with chronic rhinosinusitis with polyposis aer endoscopic sinus surgery. Int Forum Allergy Rhinol. 2016;6:233–237.
C 1 Section
of Otolaryngology, Department of Surgery, Yale School of Medicine, New Haven, CT; 2 Yale School of Medicine, New Haven, CT
Correspondence to: R. Peter Manes, MD, FACS, Section of Otolaryngology, Department of Surgery, Yale School of Medicine, P.O. Box 208041, New Haven, CT 06520–8041; e-mail: [email protected] Potential conflict of interest: None provided. Presented at the Annual ARS Meeting on September 25–26, 2015, in Dallas, TX. Public clinical trial registration: http://clinicaltrials.gov/show/NCT02194062. A Comparison of Budesonide Nasal Irrigation in Different Head Positions and Fluticasone Nasal Spray in Post-operative Functional Endoscopic Sinus Surgery Patients With Chronic Rhinosinusitis With Nasal Polyposis. Received: 28 August 2015; Revised: 23 October 2015; Accepted: 27 October 2015 DOI: 10.1002/alr.21688 View this article online at wileyonlinelibrary.com.
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International Forum of Allergy & Rhinology, Vol. 6, No. 3, March 2016
hronic rhinosinusitis (CRS) is an inflammatory condition of the lining of the nose and sinuses that lasts 12 weeks or longer with objective evidence of mucosal inflammation.1 CRS with nasal polyposis (CRSwNP) is characterized by the presence of bilateral nasal polyps in the middle meatus, among other anatomic areas. Patients with CRSwNP for whom maximal medical therapy has failed often undergo endoscopic sinus surgery (ESS). Corticosteroids are given in the postoperative period to help prevent polyps from returning. Systemic steroid therapy is associated with several well-known side effects, including hyperglycemia, poor wound healing, immunosuppression, psychiatric effects, and peptic ulcers.2 Topical nasal steroids given postoperatively also have the beneficial effect of preventing polyp formation without the associated side effects of systemic corticosteroid treatment.3
Neubauer et al.
Wei et al.,4 in a systematic review, concluded that topical nasal steroids are beneficial for CRSwNP. The literature on nonstandard topical steroids, which includes steroid rinses and intranasal steroid drops, was evaluated by Rudmik et al.5 and determined to lack enough data to recommend for regular use. There was, however, level A evidence to strongly recommend standard topical steroids in CRS. There is no consensus as to which nasal steroid and which delivery method is most effective in treating patients with CRSwNP after ESS. Standard nasal sprays, such as fluticasone, may not deliver the medication widely in the sinonasal cavity. Budesonide is available in a respule form that can be used off-label to instill the medication in the nose, through various delivery methods. In an attempt to more effectively deliver the medication, patients can change their head position to achieve better delivery. Intranasal budesonide has been shown to not suppress the hypothalamic-pituitary adrenal (HPA) axis in sprays, rinses, or respules.6 To date, reports of budesonide respules’ improved efficacy over fluticasone nasal spray in the postoperative period remain anecdotal as head to head comparisons have not been previously performed. We seek to evaluate the effects of fluticasone nasal spray, budesonide respules via a mucosal atomization device (MAD) and direct application of budesonide respules in a vertex-to-floor position in patients with CRSwNP after ESS.
Patients and methods A prospective, randomized control trial was performed on patients who have had ESS for CRSwNP. This trial was granted approval from the Yale School of Medicine Institutional Review Board and was registered as a clinical trial (http://clinicaltrials.gov/show/NCT02194062). Inclusion criteria were adult patients who had ESS for CRSwNP during the study period in whom maximal medical therapy had failed and ESS was recommended. Exclusion criteria included patients under the age of 18 years, concurrent oral corticosteroid use for other disease processes, the use of medications that accelerate or inhibit the clearance of systemic cortisol, hypersensitivity to corticosteroids, or a known history of autoimmune disease with nasal manifestations. All patients underwent bilateral maxillary antrostomy, total ethmoidectomy, sphenoidotomy and frontal sinusotomy. All patients received prednisone 40 mg daily starting 5 days prior to surgery, and tapered off prednisone for 12 days after surgery, utilizing 40 mg daily for 3 days, 30 mg daily for 3 days, 20 mg daily for 3 days, and 10 mg daily for 3 days. No drug-eluting stents were used in the study subjects. Informed consent was obtained and patients were randomized to 1 of the 3 groups using a random number generator. Group A was prescribed fluticasone nasal spray to use two 50-µg sprays to each nostril 2 times per day. Group B was prescribed budesonide respules (0.5 mg/2mL) and instructed to instill one-half into each nostril in the upright position via a MAD atomizer 2 times per day. Group C
was prescribed the same formulation and dosing schedule as group B but was instructed to instill the budesonide in the vertex-to-floor (VF) position previously described by Cannady et al.7 In order to achieve this position, patients were instructed to lean their head forward off the side of a bed for 1 minute.7 Budesonide respules are not U.S. Food and Drug Administration (FDA)-approved for intranasal use and this indication was considered “off-label.” Patients were asked to complete the 22-item Sino-Nasal Outcome Test (SNOT-22), a validated instrument that assesses symptom severity8 preoperatively, as well as 1 week, 3 weeks, 6 weeks, 2 months, 4 months, and 6 months after ESS. Additionally, at the same time points, patients underwent nasal endoscopy and were graded using the Lund-Kennedy endoscopic scoring system by the primary investigator.9 During follow-up visits, it was not known by the investigator to which group the patient had been assigned. At the time of randomization, patients were given enough medication to last through the entire study period, and the investigator purposely did not inquire about the type of nasal steroid or delivery method during follow-up visits. Questions regarding nasal steroid use were limited to ensuring patient compliance with prescribed medications. The primary endpoints were change in SNOT-22 and LundKennedy scores at 6 months. Statistical analyses were performed using SPSS version 22.0.0 for Mac (IBM Corp., Armonk, NY). Standard descriptive statistics were used to summarize demographic and response-related information. Analysis of variance (ANOVA) tests were performed to assess statistical significance for differences in mean SNOT-22 and Lund-Kennedy scores among the 3 treatment groups. Lund-Kennedy scores represent the mean of the right and left sides. Pearson chi square tests were used to determine variables associated with achieving at least a 50% reduction in SNOT-22 scores in univariate analysis. Only variables identified in univariate analysis with p ࣘ0.10 were included in a multivariable logistic regression model. All tests were 2-sided, and the final threshold for significance was set at p ࣘ0.05. Graphs were prepared using GraphPad Prism 6.0d for Mac OSX (GraphPad, La Jolla, CA).
Results Thirty-two patients were enrolled in the study, 23 of whom completed the 6-month trial. Twenty-eight patients completed 4 months and all 32 patients completed 2 months of follow-up. There were 10 males (31.3%) and 22 females (68.8%). The age was 44.31 ± 13.14 years (mean ± standard deviation [SD]). Fifteen (46.9%) had a diagnosis of asthma. Eleven (34.4%) had aspirin sensitivity. Nineteen (59.4%) had previous ESS. There were no significant differences among groups A, B, and C with respect to age, gender, asthma, aspirin sensitivity, or previous ESS. There were no reported adverse events during the study period. Group B (budesonide in the head upright position via a MAD atomizer) showed the greatest reduction in SNOT-22
International Forum of Allergy & Rhinology, Vol. 6, No. 3, March 2016
234
Fluticasone & budesonide in CRSwNP after ESS
TABLE 1. SNOT-22 scores stratified by treatment group
TABLE 2. Lund-Kennedy scores (mean of left and right)
over time
over time
Group A
Group B
Group C
Group A
Group B
Group C
Time
(mean)
(mean)
(mean)
(mean)
(mean)
(mean)
Baseline
58.70
58.33
54.30
0.642
Baseline
5.25
4.96
5.40
0.401
1 week
52.20
48.67
45.30
0.711
1 week
3.65
3.58
3.65
0.989
3 weeks
44.10
19.33
25.60
0.004
3 weeks
3.30
1.79
1.75
0.003
6 weeks
35.90
13.75
16.70
Comparison of intranasal fluticasone spray, budesonide atomizer, and budesonide respules in patients with chronic rhinosinusitis with polyposis aer endoscopic sinus surgery Paul D. Neubauer, MD1 , Zachary G. Schwam, BA2 and R. Peter Manes, MD, FACS1
Background: Nasal steroids are a critical part of the management of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) aer endoscopic sinus surgery (ESS). Increasingly, practitioners are using budesonide respules delivered to the sinonasal cavities, which is an off-label use, in lieu of traditional nasal steroids. There has been little research comparing budesonide with traditional nasal steroids and the most effective delivery method of budesonide. Methods: A randomized controlled trial was performed on patients aer ESS for CRSwNP in a tertiary care center. Patients were randomized into 1 of 3 groups: group A received fluticasone nasal spray twice daily; group B received budesonide respules via a mucosal atomization device (MAD) twice daily; and group C received budesonide respules instilled via the vertex-to-floor (VF) position twice daily. Primary endpoints were 22-item Sino-Nasal Outcome Test (SNOT-22) and Lund-Kennedy scores at 6 months. Results: Thirty-two patients were enrolled in the study, 23 of whom completed the 6-month trial. There were no significant differences among groups A, B, and C with respect to age, gender, asthma, aspirin
sensitivity, or previous ESS. Group B had a statistically significant greater reduction in SNOT-22 and Lund-Kennedy scores at the primary endpoint of 6 months compared to groups A and C. Group C had the next greatest reduction, which was statistically significant, followed by group A. Conclusion: Patients treated with budesonide aer ESS for CRSwNP had greater improvement in SNOT-22 and LundKennedy scores compared to fluticasone at 6 months. The data supports the use of budesonide respules, particularly with a MAD, over fluticasone for CRSwNP patients aer C 2015 ARS-AAOA, LLC. ESS.
Key Words: chronic disease; sinusitis; administration topical drug; offlabel use; surgical procedure endoscopic How to Cite this Article: Neubauer PD, Schwam ZG, Manes RP. Comparison of intranasal fluticasone spray, budesonide atomizer, and budesonide respules in patients with chronic rhinosinusitis with polyposis aer endoscopic sinus surgery. Int Forum Allergy Rhinol. 2016;6:233–237.
C 1 Section
of Otolaryngology, Department of Surgery, Yale School of Medicine, New Haven, CT; 2 Yale School of Medicine, New Haven, CT
Correspondence to: R. Peter Manes, MD, FACS, Section of Otolaryngology, Department of Surgery, Yale School of Medicine, P.O. Box 208041, New Haven, CT 06520–8041; e-mail: [email protected] Potential conflict of interest: None provided. Presented at the Annual ARS Meeting on September 25–26, 2015, in Dallas, TX. Public clinical trial registration: http://clinicaltrials.gov/show/NCT02194062. A Comparison of Budesonide Nasal Irrigation in Different Head Positions and Fluticasone Nasal Spray in Post-operative Functional Endoscopic Sinus Surgery Patients With Chronic Rhinosinusitis With Nasal Polyposis. Received: 28 August 2015; Revised: 23 October 2015; Accepted: 27 October 2015 DOI: 10.1002/alr.21688 View this article online at wileyonlinelibrary.com.
233
International Forum of Allergy & Rhinology, Vol. 6, No. 3, March 2016
hronic rhinosinusitis (CRS) is an inflammatory condition of the lining of the nose and sinuses that lasts 12 weeks or longer with objective evidence of mucosal inflammation.1 CRS with nasal polyposis (CRSwNP) is characterized by the presence of bilateral nasal polyps in the middle meatus, among other anatomic areas. Patients with CRSwNP for whom maximal medical therapy has failed often undergo endoscopic sinus surgery (ESS). Corticosteroids are given in the postoperative period to help prevent polyps from returning. Systemic steroid therapy is associated with several well-known side effects, including hyperglycemia, poor wound healing, immunosuppression, psychiatric effects, and peptic ulcers.2 Topical nasal steroids given postoperatively also have the beneficial effect of preventing polyp formation without the associated side effects of systemic corticosteroid treatment.3
Neubauer et al.
Wei et al.,4 in a systematic review, concluded that topical nasal steroids are beneficial for CRSwNP. The literature on nonstandard topical steroids, which includes steroid rinses and intranasal steroid drops, was evaluated by Rudmik et al.5 and determined to lack enough data to recommend for regular use. There was, however, level A evidence to strongly recommend standard topical steroids in CRS. There is no consensus as to which nasal steroid and which delivery method is most effective in treating patients with CRSwNP after ESS. Standard nasal sprays, such as fluticasone, may not deliver the medication widely in the sinonasal cavity. Budesonide is available in a respule form that can be used off-label to instill the medication in the nose, through various delivery methods. In an attempt to more effectively deliver the medication, patients can change their head position to achieve better delivery. Intranasal budesonide has been shown to not suppress the hypothalamic-pituitary adrenal (HPA) axis in sprays, rinses, or respules.6 To date, reports of budesonide respules’ improved efficacy over fluticasone nasal spray in the postoperative period remain anecdotal as head to head comparisons have not been previously performed. We seek to evaluate the effects of fluticasone nasal spray, budesonide respules via a mucosal atomization device (MAD) and direct application of budesonide respules in a vertex-to-floor position in patients with CRSwNP after ESS.
Patients and methods A prospective, randomized control trial was performed on patients who have had ESS for CRSwNP. This trial was granted approval from the Yale School of Medicine Institutional Review Board and was registered as a clinical trial (http://clinicaltrials.gov/show/NCT02194062). Inclusion criteria were adult patients who had ESS for CRSwNP during the study period in whom maximal medical therapy had failed and ESS was recommended. Exclusion criteria included patients under the age of 18 years, concurrent oral corticosteroid use for other disease processes, the use of medications that accelerate or inhibit the clearance of systemic cortisol, hypersensitivity to corticosteroids, or a known history of autoimmune disease with nasal manifestations. All patients underwent bilateral maxillary antrostomy, total ethmoidectomy, sphenoidotomy and frontal sinusotomy. All patients received prednisone 40 mg daily starting 5 days prior to surgery, and tapered off prednisone for 12 days after surgery, utilizing 40 mg daily for 3 days, 30 mg daily for 3 days, 20 mg daily for 3 days, and 10 mg daily for 3 days. No drug-eluting stents were used in the study subjects. Informed consent was obtained and patients were randomized to 1 of the 3 groups using a random number generator. Group A was prescribed fluticasone nasal spray to use two 50-µg sprays to each nostril 2 times per day. Group B was prescribed budesonide respules (0.5 mg/2mL) and instructed to instill one-half into each nostril in the upright position via a MAD atomizer 2 times per day. Group C
was prescribed the same formulation and dosing schedule as group B but was instructed to instill the budesonide in the vertex-to-floor (VF) position previously described by Cannady et al.7 In order to achieve this position, patients were instructed to lean their head forward off the side of a bed for 1 minute.7 Budesonide respules are not U.S. Food and Drug Administration (FDA)-approved for intranasal use and this indication was considered “off-label.” Patients were asked to complete the 22-item Sino-Nasal Outcome Test (SNOT-22), a validated instrument that assesses symptom severity8 preoperatively, as well as 1 week, 3 weeks, 6 weeks, 2 months, 4 months, and 6 months after ESS. Additionally, at the same time points, patients underwent nasal endoscopy and were graded using the Lund-Kennedy endoscopic scoring system by the primary investigator.9 During follow-up visits, it was not known by the investigator to which group the patient had been assigned. At the time of randomization, patients were given enough medication to last through the entire study period, and the investigator purposely did not inquire about the type of nasal steroid or delivery method during follow-up visits. Questions regarding nasal steroid use were limited to ensuring patient compliance with prescribed medications. The primary endpoints were change in SNOT-22 and LundKennedy scores at 6 months. Statistical analyses were performed using SPSS version 22.0.0 for Mac (IBM Corp., Armonk, NY). Standard descriptive statistics were used to summarize demographic and response-related information. Analysis of variance (ANOVA) tests were performed to assess statistical significance for differences in mean SNOT-22 and Lund-Kennedy scores among the 3 treatment groups. Lund-Kennedy scores represent the mean of the right and left sides. Pearson chi square tests were used to determine variables associated with achieving at least a 50% reduction in SNOT-22 scores in univariate analysis. Only variables identified in univariate analysis with p ࣘ0.10 were included in a multivariable logistic regression model. All tests were 2-sided, and the final threshold for significance was set at p ࣘ0.05. Graphs were prepared using GraphPad Prism 6.0d for Mac OSX (GraphPad, La Jolla, CA).
Results Thirty-two patients were enrolled in the study, 23 of whom completed the 6-month trial. Twenty-eight patients completed 4 months and all 32 patients completed 2 months of follow-up. There were 10 males (31.3%) and 22 females (68.8%). The age was 44.31 ± 13.14 years (mean ± standard deviation [SD]). Fifteen (46.9%) had a diagnosis of asthma. Eleven (34.4%) had aspirin sensitivity. Nineteen (59.4%) had previous ESS. There were no significant differences among groups A, B, and C with respect to age, gender, asthma, aspirin sensitivity, or previous ESS. There were no reported adverse events during the study period. Group B (budesonide in the head upright position via a MAD atomizer) showed the greatest reduction in SNOT-22
International Forum of Allergy & Rhinology, Vol. 6, No. 3, March 2016
234
Fluticasone & budesonide in CRSwNP after ESS
TABLE 1. SNOT-22 scores stratified by treatment group
TABLE 2. Lund-Kennedy scores (mean of left and right)
over time
over time
Group A
Group B
Group C
Group A
Group B
Group C
Time
(mean)
(mean)
(mean)
(mean)
(mean)
(mean)
Baseline
58.70
58.33
54.30
0.642
Baseline
5.25
4.96
5.40
0.401
1 week
52.20
48.67
45.30
0.711
1 week
3.65
3.58
3.65
0.989
3 weeks
44.10
19.33
25.60
0.004
3 weeks
3.30
1.79
1.75
0.003
6 weeks
35.90
13.75
16.70
