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Diferentes tipos de corticosteroides intranasales para la rinosinusitis crónica

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Referencias

Chur 2013 {published data only}

Chur V, Small CB, Stryszak P, Teper A. Mometasone furoate nasal spray is safe for the treatment of nasal polyps in pediatric subjects 6‐17 years of age. Journal of Allergy & Clinical Immunology 2010;25(Suppl 2):AB101.
Chur V, Small CB, Stryszak P, Teper A. Safety of mometasone furoate nasal spray in the treatment of nasal polyps in children. Pediatric Allergy and Immunology 2013;24(1):33‐8. [PUBMED: 23331528]

Demirel 2008 {published data only}

Demirel T, Orhan KS, Keles N, Deger K. Comparison of the efficacy of nasal drop and nasal spray applications of fluticasone propionate in nasal polyps. Kulak Burun Bogaz Ihtisas Dergisi: KBB [Journal of Ear, Nose, and Throat] 2008;18(1):1‐6. [PUBMED: 18443395]

Filipovic 2006 {published data only}

Filipovic MD, Cekic SS. A comparison of fluticasone propionate (FP) and mometasone furoate (MF) nasal spray in the treatment of nasal polyposis associated with asthma [Abstract]. European Respiratory Society International Congress; 2006 Sep 2‐6; Munich, Germany. 2006:314s.

Holmberg 1997 {published data only}

Holmberg K, Juliusson S, Balder B, Smith DL, Richards DH, Karlsson G. Fluticasone propionate aqueous nasal spray in the treatment of nasal polyposis. Annals of Allergy, Asthma, and Immunology 1997;78(3):270‐6. [PUBMED: 9087151]

Johansen 1993 {published data only}

Vendelo Johansen L, Illum P, Kristensen S, Winther L, Vang Petersen S, Synnerstad B. The effect of budesonide (Rhinocort) in the treatment of small and medium‐sized nasal polyps. Clinical Otolaryngology and Allied Sciences 1993;18(6):524‐7. [PUBMED: 8877234]

Lund 1998 {published data only}

Lund VJ, Flood J, Sykes AP, Richards DH. Effect of fluticasone in severe polyposis. Archives of Otolaryngology ‐‐ Head and Neck Surgery 1998;124(5):513‐8. [PUBMED: 9604976]

Penttila 2000 {published data only}

Penttila M, Holstrom M, Poulsen P, Hollingworth K. The efficacy and tolerability of fluticasone propionate (FP) nasal drops 400fig once daily and twice daily compared with placebo in the treatment of nasal polyposis. Allergy 1998;53(Suppl 43):109.
Penttila M, Poulsen P, Hollingworth K, Holmstrom M. Dose‐related efficacy and tolerability of fluticasone propionate nasal drops 400 microg once daily and twice daily in the treatment of bilateral nasal polyposis: a placebo‐controlled randomized study in adult patients. Clinical and Experimental Allergy 2000;30(1):94‐102. [PUBMED: 10606936]

Small 2005 {published data only}

Bloom M, Staudinger H. Effect of mometasone furoate nasal spray (MFNS) on nasal polyposis. Journal of Allergy and Clinical Immunology 2004;113(2 Suppl):S282.
Bloom M, Staudinger H. Effect of mometasone furoate nasal spray on nasal polyposis. Proceedings of the XXIII Congress of the European Academy of Allergology and Clinical Immunology (EAACI); 2004 Jun 12‐16; Amsterdam, The Netherlands. 2004:Abstract No 279.
Small CB, Hernandez J, Reyes A, Schenkel E, Damiano A, Stryszak P, et al. Efficacy and safety of mometasone furoate nasal spray in nasal polyposis. Journal of Allergy and Clinical Immunology 2005;116(6):1275‐81. [PUBMED: 16337459]

Stjarne 2006 {published data only}

Bloom M, Staudinger H. Effect of mometasone furoate nasal spray (MFNS) on nasal polyposis. Journal of Allergy and Clinical Immunology 2004;113(2 Suppl):S282.
Bloom M, Staudinger H. Effect of mometasone furoate nasal spray on nasal polyposis. Proceedings of the XXIII Congress of the European Academy of Allergology and Clinical Immunology (EAACI); 2004 Jun 12‐16; Amsterdam, The Netherlands. 2004:Abstract No 279.
Stjarne P, Mosges R, Jorissen M, Passali D, Bellussi L, Staudinger H, et al. A randomized controlled trial of mometasone furoate nasal spray for the treatment of nasal polyposis. Archives of Otolaryngology ‐‐ Head and Neck Surgery 2006;132(2):179‐85. [PUBMED: 16490876]

Bross‐Soriano 2004 {published data only}

Bross‐Soriano D, Arrieta‐Gomez JR, Prado‐Calleros H. Infections after endoscopic polypectomy using nasal steroids. Otolaryngology ‐ Head and Neck Surgery 2004;130(3):319‐22.

Cannady 2005 {published data only}

Cannady SB, Batra PS, Citardi MJ, Lanza DC. Comparison of delivery of topical medications to the paranasal sinuses via "vertex‐to‐floor" position and atomizer spray after FESS. Otolaryngology ‐ Head and Neck Surgery 2005;133(5):735‐40.

Dijkstra 2004 {published data only}

Dijkstra MD, Ebbens FA, Poublon RML, Fokkens WJ. Fluticasone propionate aqueous nasal spray does not influence the recurrence rate of chronic rhinosinusitis and nasal polyps 1 year after functional endoscopic sinus surgery. Clinical and Experimental Allergy 2004;34(9):1395‐400.
Dijkstra MD, Poublon RML, Fokkens WJ. The role of topical corticosteroids after functional endoscopic sinus surgery for chronic sinusitis and/or nasal polyps. Clinical Otolaryngology and Allied Sciences 2001;26(4):341‐2.

Filiaci 2000 {published data only}

Filiaci F, Passali D, Puxeddu R, Schrewelius C. A randomized controlled trial showing efficacy of once daily intranasal budesonide in nasal polyposis. Rhinology 2000;38(4):185‐90.

Fowler 2002 {published data only}

Fowler PD, Gazis AG, Page SR, Jones NS. A randomized double‐blind study to compare the effects of nasal fluticasone and betamethasone on the hypothalamo‐pituitary‐adrenal axis and bone turnover in patients with nasal polyposis. Clinical Otolaryngology and Allied Sciences 2002;27(6):489‐93.

Giger 2003 {published data only}

Giger R, Pasche P, Cheseaux C, Cantini L, Rossetti A, Landis BN, et al. Comparison of once‐ versus twice‐daily use of beclomethasone dipropionate aqueous nasal spray in the treatment of allergic and non‐allergic chronic rhinosinusitis. European Archives of Oto‐Rhino‐Laryngology 2003;260(3):135‐40. [PUBMED: 12687385]

Jankowski 2001 {published data only}

Jankowski R, Schrewelius C, Bonfils P, Saban Y, Gilain L, Prades JM, et al. Efficacy and tolerability of budesonide aqueous nasal spray treatment in patients with nasal polyps. Archives of Otolaryngology‐‐Head & Neck Surgery 2001;127(4):447‐52.

Keith 1995 {published data only}

Keith PK, Conway M, Evans S, Edney P, Jennings B, Anderson B, et al. A double‐blind comparison of intranasal budesonide dry powder vs placebo in nasal polyposis. Journal of Allergy and Clinical Immunology 1995;95(1 Part 2):204.

Lildholdt 1995 {published data only}

Lildholdt T, Rundcrantz H, Lindqvist N. Efficacy of topical corticosteroid powder for nasal polyps: a double‐blind, placebo‐controlled study of budesonide. Clinical Otolaryngology and Allied Sciences 1995;20(1):26‐30.

NCT00788463 {published and unpublished data}

NCT00788463. A comparison of beclomethasone aqueous spray and aerosol delivery systems in nasal polyps. https://clinicaltrials.gov/show/NCT00788463 (accessed 27 February 2016).

NCT01405339 {published data only}

NCT01405339. Budesonide application via mucosal atomization device as a treatment for chronic rhinosinusitis when utilized as a topical nasal steroid spray. https://clinicaltrials.gov/show/NCT01405339 (accessed 22 February 2016).

NCT01623310 {published data only}

IncOu, NCT01623310. Study evaluating the safety of intranasal administration of 400 μg of fluticasone propionate twice a day (bid) using a novel bi‐directional device in subjects with chronic sinusitis with or without nasal polyps. https://clinicaltrials.gov/show/NCT01623310 (accessed 22 February 2016).

NCT02194062 {published data only}

NCT02194062. Comparison of nasal steroids after FESS in CRSwNP. https://clinicaltrials.gov/show/NCT02194062 (accessed on 27 February 2016).

Raghavan 2006 {published data only}

Raghavan U, Jones NS. A prospective randomized blinded cross‐over trial using nasal drops in patients with nasal polyposis: an evaluation of effectiveness and comfort level of two head positions. American Journal of Rhinology 2006;20(4):397‐400.

Reychler 2015 {published data only}

Reychler G, Colbrant C, Huart C, Le Guellec S, Vecellio L, Liistro G, et al. Effect of three‐drug delivery modalities on olfactory function in chronic sinusitis. Laryngoscope 2015;125(3):549‐55.
Reychler G, Colbrant C, Huart C, Le Guellec S, Vecellio L, Rombaux P. Comparison of three modalities of corticosteroids administration in chronic rhinosinusitis. European Respiratory Journal 2014;44 Suppl 58:Abstract.

Singhal 2008 {published data only}

Singhal D, Hissaria P, Smith W. Three methods of delivery of nasal corticosteroids in chronic sinusitis: a pilot study. Internal Medicine Journal 2008;38(S6):A154.

Toft 1982 {published data only}

Toft A, Wihl JA, Toxman J, Mygind N. Double‐blind comparison between beclomethasone dipropionate as aerosol and as powder in patients with nasal polyposis. Clinical Allergy 1982;12(4):391‐401.
Wihl JA. Topical corticosteroids and nasal reactivity. European Journal of Respiratory Diseases 1982;122:205‐10.

Tos 1998 {published data only}

Tos M, Svendstrup F, Arndal H, Orntoft S, Jakobsen J, Borum P, et al. Efficacy of an aqueous and a powder formulation of nasal budesonide compared in patients with nasal polyps. American Journal of Rhinology 1998;12(3):183‐9.

Wang 2012 {published data only}

Wang C, Lou H, Lou W, Zhang L. The efficacy and safety of a short course of budesonide inhalation suspension via transnasal nebulization in chronic rhinosinusitis with nasal polyps. Lin chuang er bi yan hou tou jing wai ke za zhi [Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery] 2012;26(8):347‐50.

Referencias de los estudios en espera de evaluación

Bachert 2004 {published data only}

Bachert C. Efficacy of budesonide powder treatments in nasal polyposis. Proceedings of the 3rd International Consensus Conference on Nasal Polyposis. 2004 Apr 23‐25; Brussels, Belgium. 2004.

Meln 2004 {published data only}

Meln I, Johansson L, Holmberg K, Stierna P, Bende M. Results from treatment with topical steroids. Proceedings of the 3rd International Consensus Conference on Nasal Polyposis; 2004 23‐25 Apr; Brussels, Belgium. 2004:335.

Pisano 2000 {published data only}

Pisano G. Management of nasal polyposis: efficacy of intranasal corticosteroid with hypertonic solution. Proceedings of the XVIII Congress of European Rhinologic Society and XIX International Symposium on Infection and Allergy of the Nose; 2000 25‐29 Jun; Barcelona, Spain. 2000:Abstract No. 414.

Reim 2005 {published data only}

Reim L. Mometasone furoate for the treatment of nasal polyps. Medizinische Welt 2005;56:224.

NCT01622569 {published data only}

NCT01622569. Study evaluating the efficacy and safety of intranasal administration of 100, 200, and 400 μg of fluticasone propionate twice a day (bid) using a novel bi directional device in subjects with bilateral nasal polyposis followed by an 8‐week open‐label extension phase to assess safety. https://clinicaltrials.gov/show/NCT01622569 (accessed 27 February 2016).

NCT01624662 {published data only}

NCT01624662. Efficacy and safety study of intranasal administration of 100, 200, and 400 μg of fluticasone propionate twice a day (bid) using a novel bi directional device in subjects with bilateral nasal polyposis followed by an 8‐week open‐label extension phase to assess safety. https://clinicaltrials.gov/show/NCT01624662 (accessed 27 February 2016).

NCT01946711 {published and unpublished data}

NCT01946711. A randomised, open, controlled pilot study to investigate the efficacy and safety of Buparid/PARI SINUS versus Budes® nasal spray in the therapy of chronic rhinosinusitis (CRS) with polyposis nasi in adult patients. https://clinicaltrials.gov/ct2/show/NCT01946711 (accessed 27 February 2016).

Balk 2012

Balk EM, Earley A, Patel K, Trikalinos TA, Dahabreh IJ. Empirical assessment of within‐arm correlation imputation in trials of continuous outcomes [Internet]. Report No.: 12(13)‐EHC141‐EF. AHRQ Methods for Effective Health Care. Rockville (MD): Agency for Healthcare Research and Quality, 2012.

Benninger 2003

Benninger MS, Ferguson BJ, Hadley JA, Hamilos DL, Jacobs M, Kennedy DW, et al. Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngology ‐ Head and Neck Surgery 2003;129(Suppl 3):S1‐32.

Cho 2012

Cho SH, Hong SJ, Han B, Lee SH, Suh L, Norton J, et al. Age‐related differences in the pathogenesis of chronic rhinosinusitis. Journal of Allergy and Clinical Immunology 2012;129(3):858‐60.e2.

Chong 2016a

Chong LY, Head K, Hopkins C, Philpott C, Schilder AGM, Burton MJ. Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD011996.pub2]

Chong 2016b

Chong LY, Head K, Hopkins C, Philpott C, Glew S, Scadding G, et al. Saline irrigation for chronic rhinosinusitis. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD011995.pub2]

Cohen 1988

Cohen J. Statistical Power Analysis in the Behavioral Sciences. 2nd Edition. Hillsdale (NJ): Lawrence Erlbaum Associates, Inc., 1988.

DeMarcantonio 2011

DeMarcantonio MA, Han JK. Nasal polyps: pathogenesis and treatment implications. Otolaryngologic Clinics of North America 2011;44(3):685‐95, ix.

Ebbens 2010

Ebbens FA, Toppila‐Salmi SK, Renkonen JA, Renkonen RL, Mullol J, van Drunen CM, et al. Endothelial L‐selectin ligand expression in nasal polyps. Allergy 2010;65(1):95‐102.

Ebbens 2011

Ebbens FA, Toppila‐Salmi S, de Groot EJ, Renkonen J, Renkonen R, van Drunen CM, et al. Predictors of post‐operative response to treatment: a double blind placebo controlled study in chronic rhinosinusitis patients. Rhinology 2011;49(4):413‐9.

Egger 1997

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ (Clinical research ed.) 1997;315(7109):629‐34. [PUBMED: 9310563]

EPOS 2012

Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Rhinology. Supplement 2012;50 Suppl 23:1‐298.

Fokkens 2007

Fokkens W, Lund V, Mullol J. European position paper on rhinosinusitis and nasal polyps 2007. Rhinology 2007;45(Suppl 20):1‐139.

Gliklich 1995

Gliklich RE, Metson R. The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngology ‐ Head and Neck Surgery 1995;113(1):104‐9.

Grobler 2008

Grobler A, Weitzel EK, Buele A, Jardeleza C, Cheong YC, Field J, et al. Pre‐ and postoperative sinus penetration of nasal irrigation. Laryngoscope 2008;118(11):2078‐81.

Hamilos 2000

Hamilos DL. Chronic sinusitis. Journal of Allergy and Clinical Immunology 2000;106:213‐27.

Handbook 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Harvey 2009

Harvey RJ, Debnath N, Srubiski A, Bleier B, Schlosser RJ. Fluid residuals and drug exposure in nasal irrigation. Otolaryngology ‐ Head and Neck Surgery 2009;141(6):757‐61.

Hastan 2011

Hastan D, Fokkens WJ, Bachert C, Newson RB, Bislimovska J, Bockelbrink A, et al. Chronic rhinosinusitis in Europe ‐ an underestimated disease. A GA2LEN study. Allergy 2011;66(9):1216‐23.

Head 2016a

Head K, Chong LY, Hopkins C, Philpott C, Burton MJ, Schilder AGM. Short‐course oral steroids alone for chronic rhinosinusitis. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD011991.pub2]

Head 2016b

Head K, Chong LY, Hopkins C, Philpott C, Schilder AGM, Burton MJ. Short‐course oral steroids as an adjunct therapy for chronic rhinosinusitis. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD011992.pub2]

Head 2016c

Head K, Chong LY, Piromchai P, Hopkins C, Philpott C, Schilder AGM, et al. Systemic and topical antibiotics for chronic rhinosinusitis. Cochrane Database of Systematic Reviews 2016, Issue 4. [DOI: 10.1002/14651858.CD011994.pub2]

Kalish 2012

Kalish L, Snidvongs K, Sivasubramaniam R, Cope D, Harvey RJ. Topical steroids for nasal polyps. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.CD006549.pub2]

Kern 2008

Kern RC, Conley DB, Walsh W, Chandra R, Kato A, Tripathi‐Peters A, et al. Perspectives on the etiology of chronic rhinosinusitis: an immune barrier hypothesis. American Journal of Rhinology 2008;22(6):549‐59.

Keswani 2012

Keswani A, Chustz RT, Suh L, Carter R, Peters AT, Tan BK, et al. Differential expression of interleukin‐32 in chronic rhinosinusitis with and without nasal polyps. Allergy 2012;67(1):25‐32.

Larsen 2004

Larsen P, Tos M. Origin of nasal polyps: an endoscopic autopsy study. Laryngoscope 2004;114(4):710‐9.

McNally 1997

McNally PA, White MW, Kaliner MA. Sinusitis in an allergists' office: analysis of 2000 consecutive cases. Allergy and Asthma Proceedings 1997;18:169‐75.

Mullol 2009

Mullol J. Corticosteroid treatment in chronic rhinosinusitis: the possibilities and the limits. Immunology and Allergy Clinics of North America 2009;29(4):657‐68.

Ragab 2004

Ragab SM, Lund VJ, Scadding G. Evaluation of the medical and surgical treatment of chronic rhinosinusitis: a prospective, randomised, controlled trial. Laryngoscope 2004;114(5):923‐30.

Ragab 2010

Ragab SM, Lund VJ, Scadding G, Saleh HA, Khalifa MA. Impact of chronic rhinosinusitis therapy on quality of life: a prospective randomized controlled trial. Rhinology 2010;48(3):305‐11.

RevMan 2014 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Snidvongs 2011

Snidvongs K, Kalish L, Sacks R, Craig JC, Harvey RJ. Topical steroid for chronic rhinosinusitis without polyps. Cochrane Database of Systematic Reviews 2011, Issue 8. [DOI: 10.1002/14651858.CD009274]

Soler 2010

Soler ZM, Smith TL. Quality‐of‐life outcomes after endoscopic sinus surgery: how long is long enough?. Otolaryngology ‐ Head and Neck Surgery 2010;143(5):621‐5.

Spector 1998

Spector SL, Bernstein IL, Li JT, Berger WE, Kaliner MA, Schuller DE, et al. Parameters for the diagnosis and management of sinusitis. Journal of Allergy and Clinical Immunology 1998;102(6 Pt 2):S107‐44.

Tan 2011

Tan BK, Li QZ, Suh L, Kato A, Conley DB, Chandra RK, et al. Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps. Journal of Allergy and Clinical Immunology 2011;128(6):1198‐206.e1.

Thomas 2013

Thomas WW, Harvey RJ, Rudmik L, Hwang PH, Schlosser RJ. Distribution of topical agents to the paranasal sinuses: an evidence‐based review with recommendations. International Forum of Allergy and Rhinology 2013;3(9):691‐703.

Tomassen 2011

Tomassen P, Van Zele T, Zhang N, Perez‐ Novo C, Van Bruaene N, Gevaert P, et al. Pathophysiology of chronic rhinosinusitis. Proceedings of the American Thoracic Society 2011;8(1):115‐20.

van Drunen 2009

van Drunen CM, Reinartz SM, Wigman J, Fokkens W. Inflammation in chronic rhinosinusitis and nasal polyposis. Immunology and Allergy Clinics of North America 2009;29(4):621‐9.

Zhang 2008

Zhang N, Van Zele T, Perez‐Novo C, Van Bruaene N, Holtappels G, DeRuyck N, et al. Different types of T‐effector cells orchestrate mucosal inflammation in chronic sinus disease. Journal of Allergy and Clinical Immunology 2008;122(5):961‐8.

Zhang 2009

Zhang XH, Lu X, Long XB, You XJ, Gao QX, Cui YH, et al. Chronic rhinosinusitis with and without nasal polyps is associated with decreased expression of glucocorticoid‐induced leucine zipper. Clinical and Experimental Allergy 2009;39(5):647‐54.

Referencias de otras versiones publicadas de esta revisión

Chong 2015

Chong LY, Head K, Hopkins C, Philpott C, Burton MJ. Different types of intranasal steroids for chronic rhinosinusitis. Cochrane Database of Systematic Reviews 2015, Issue 12. [DOI: 10.1002/14651858.CD011993]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Chur 2013

Methods

4‐arm, "double blind", international, multicentre, parallel‐group RCT, with a 4‐month duration of treatment and follow‐up

Participants

Location: 9 countries: Colombia, Guatemala, Honduras, Panama, Peru, Russia, South Africa, Ukraine, United States. No. of sites not presented.

Setting of recruitment and treatment: not stated

Sample size:

6 to 11 years

  • Number randomised (6 to 11 years): 18 in intervention 1 (once daily), 18 in intervention 2 (twice daily), 10 in comparison (placebo)

  • Number completed (6 to 11 years): no information

12 to 17 years

  • Number randomised (12 to 17 years): 32 in intervention 1, 33 in intervention 2, 16 in comparison

  • Number completed (12 to 17 years): no information

Participant (baseline) characteristics:

6 to 11 years

  • Age: twice daily group – 9.6, once daily group – 9.7, placebo group – 12.7

  • Gender M/F: twice daily group – 5/13, once daily group – 8/10, placebo group – 12/14

  • Main diagnosis: nasal polyps

  • Polyps status: 100% with polyps

  • Previous sinus surgery status: no information

Other important effect modifiers:

  • Asthma: twice daily group – 1, once daily group – 3, placebo group – 6

  • Eosinophilic: twice daily group – 3, once daily group – 5, placebo group – 9

12 to 17 years

  • Age: twice daily group – 14.4, once daily group – 14.4, placebo group – 12.7

  • Gender: twice daily group – 15/18, once daily group – 14/18, placebo group – 12/14

  • Main diagnosis: bilateral nasal polyps

  • Polyps status: 100% with polyps

  • Previous sinus surgery status: no information

Other important effect modifiers:

  • Asthma: twice daily group – 4, once daily group – 9, placebo group – 6

  • Eosinophilic: twice daily group – 3, once daily group – 9, placebo group – 9

Inclusion criteria: children aged 6 to 17 years with nasal polyposis
Exclusion criteria:

  • Children younger than 6 years

  • Antrochoanal polyps, cystic fibrosis, acute rhinosinusitis, rhinitis medicamentosa, dyskinetic ciliary syndromes and aspirin allergy

  • Patients with asthma who received inhaled corticosteroids were required to be on no more than a moderate dosage regimen as defined by the 2005 Global Initiative for Asthma Guidelines (GINA) for 1 month before screening and to remain on it throughout the study (16); other forms of corticosteroids were prohibited

Interventions

6 to 11 years

Intervention 1 (n = 18): mometasone furoate nasal spray, 100 µg once per day for 4 months

Intervention 2 (n = 18): mometasone furoate nasal spray, 100 µg twice per day for 4 months

Comparator group (n = 10): placebo once or twice daily (combined), for 4 months

12 to 17 years

Intervention 1 (n = 26): mometasone furoate nasal spray, 200 µg once per day for 4 months

Intervention 2 (n = 32): mometasone furoate nasal spray, 200 µg twice per day for 4 months

Comparator group (n = 16): placebo once or twice daily (combined) for 4 months

Use of additional interventions (common to both treatment arms): inhaled corticosteroids for patients with asthma (up to the equivalent of a moderate dosage regimen according to GINA 2005)

Outcomes

Outcomes of interest in the review:

All outcomes were measured at 4 months

Primary outcomes:

1. Participants rated signs/symptoms including nasal congestion/obstruction, anterior rhinorrhoea/postnasal drip and loss of sense of smell; rated daily by participants on a 4‐point scale

2. Significant adverse effect: epistaxis

Secondary outcomes:

3. Other adverse effects: local irritation (including oral thrush, sore throat)

4. Polyps size, no details on scores used

Other outcomes reported by the study:

  • (Primary outcome) Effects on hypothalamic‐pituitary‐adrenal (HPA) axis function (24‐hour urinary free cortisol change from baseline and 24‐hour urinary free cortisol corrected for creatinine/adverse events)

  • Investigator‐evaluated polyp size (on a 4‐point scale)

  • Investigator assessment of overall therapeutic response (on a 5‐point scale ranging from 0 (complete relief) to 4 (no relief)

Funding sources

"Editorial assistance was provided by Andrew Horgan, PhD, of AdelphiEden Health Communications, New York, NY. This assistance was funded by Merck Sharpe and Dohme Corp."

Declarations of interest

No information provided. (One of the authors of was affiliated with Merck Sharpe and Dome; which was Schering‐Plough in 2008 at the time of the study).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Subjects were randomly assigned to one of four treatment groups in a 4:4:1:1 ratio... stratified by age"

Comment: pg 34, col 1, para 4

Allocation concealment (selection bias)

Unclear risk

Comment: no information about allocation concealment provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "received MFNS 200 mcg once daily, MFNS 200 mcg twice daily, placebo once daily, or placebo twice daily"

Comment: the abstract mentioned "double‐blind" and a placebo was used. However, instead of using a double‐dummy design, where all participants received the medication twice daily (with a placebo given for those who had once daily treatment), groups either had medication once or twice daily. Therefore, there is no blinding for participants in terms of knowing whether they are on the once daily or twice daily regimen.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: (as above)

Comment: most of the outcomes are patient‐reported and therefore blinding of outcome assessment is affected

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: no information about loss to follow‐up or exclusion. However, only 119/127 (93%) of randomised patients were included in their primary endpoint analysis. There were more exclusions/drop‐outs from the 100 μg group compared with the higher‐dose group (6 (12%) versus 1) but no reasons were provided.

Adverse effects and symptoms were reported based on 127 participants. Unclear whether there were any imputations.

Selective reporting (reporting bias)

High risk

Quote: "No statistical analysis of efficacy end points was pre‐specified in the study protocol, and only descriptive efficacy statistics were collected."

Comment: the protocol was identified (NCT00378378) and the purpose as set out in the protocol was "to evaluate the safety and efficacy of Nasonex® (Mometasone Furoate Nasal Spray(MFNS)) in the treatment of nasal polyps in pediatric subjects between the ages of 6 and less than 18 years old. Safety will be the primary focus of this study." The study only reported the change from baseline in points and percentages but not the standard deviations and P values. The values from the treatment groups were very similar to the placebo group for some outcomes (e.g. ‐43% for once daily versus ‐42% for placebo for the outcome of rhinorrhoea). Poor reporting due to lack of beneficial effects cannot be ruled out.

Other bias

Unclear risk

Comment: there is no information regarding the validation of the symptom score

Demirel 2008

Methods

3‐arm, "double‐blind", parallel‐group RCT, with a 12‐week duration of treatment and follow‐up

Participants

Location: Turkey, 1 site

Setting of recruitment and treatment: Department of Otorhinolaryngology, Faculty of Medicine, Istanbul University

Sample size:

  • Number randomised: 11 in once daily group, 15 in twice daily group

  • Number completed: 10 in once daily group, 13 in twice daily group

Participant (baseline) characteristics:

  • Mean age ± SD (range): twice daily group: 32.5 ± 7.8 (20 to 43), once daily group: 49.8 ± 12.3 (30 to 63)

  • Gender M/F: twice daily group: 5/8, once daily group: 6/4

  • Main diagnosis: bilateral nasal polyposis

  • Polyps status: 100% with polyps

  • Previous sinus surgery status (polypectomy): twice daily group: 5 (38%), once daily group: 6 (60%)

Other important effect modifiers:

  • Aspirin sensitivity: twice daily group: 2 (15%), once daily group: 4 (40%)

Inclusion criteria: age 16 years or over with bilateral nasal polyposis
Exclusion criteria: presence of a purulent nasal discharge, allergic rhinitis, severe asthma, cystic fibrosis, unstable or other serious concurrent disease, psychological disorders, aspirin intolerance, Churg‐Strauss Syndrome, Kartagener's syndrome or Young's syndrome; the use of an oral or depot corticosteroid during the previous 3 months or astemizole within 6 weeks before the study or other antihistamines within 48 hours before the last presentation, required maintenance of parenteral or intranasal corticosteroids or cromolyn sodium (sodium cromoglycate), and the presence of any contraindication to corticosteroids. In addition, women of child‐bearing age were included if they were not pregnant or lactating, and were warned to take adequate contraceptive measures to avoid becoming pregnant during the study.

Interventions

Intervention (n = 15): fluticasone proportionate nasal drops, 800 μg/day (400 μg twice daily) for 12 weeks

Control (n = 11): fluticasone proportionate nasal drops, 400 μg once daily for 12 weeks

Use of additional interventions (common to all treatment arms): some patients underwent polypectomy at the end of trial

Outcomes

Outcomes of interest in the review:

Secondary outcomes:

1) Polyps size, by rigid endoscope at 12 weeks. A 4‐point scoring system was used (0 to 3) (definitions: 0 ‐ no polyps, 1 ‐ mild polyposis – small polyp not reaching to upper edge of the inferior turbinate and causing only slight obstruction; 2 – moderate polyposis – medium polyp reaching between the upper and lower inferior turbinate and causing troublesome obstruction; 3 – severe polyposis – large polyp reaching below the lower edge of the inferior turbinate and causing almost/total blockage)

Other outcomes reported by the study:

  • Nasal volumes by acoustic rhinometry

  • Physician‐rated clinical symptom scores (nasal blockage score, rhinitis symptom score, nasal discomfort score and smelling score); physician assessed weekly on a 4‐point scale (0 (none) to 3 (severe))

Funding sources

No information provided

Declarations of interest

No information provided

Notes

One of the arms (fluticasone propionate nasal spray 200 µg per day given in 2 divided doses) is not relevant to this review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "…randomly divided…"

Comment: pg 3, col 1, para 3

No further information provided

Baseline age does not appear to be balanced: the mean age of the 400 µg twice daily nasal group was about 17 years younger

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "…double‐blind.."

Comment: pg 1, col 1, para 2 says that the study was double‐blinded but the interventions were given in a different format (nasal spray versus nasal drops) and at different frequencies (1 versus 2 times per day) so it is difficult to see how either the personnel or participants were blind to the intervention). There was no mention of placebo.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no mention of placebo used; difficult to see how investigators and/or participants can be blinded to treatment intervention

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: 34 of 39 people randomised completed the trial (87%) but those who did not complete (of which 4/5 were due to worsening of the condition) were not included in the outcomes

Selective reporting (reporting bias)

High risk

Comment: numerical information was not well provided; most information for symptoms was presented as figures

Other bias

Unclear risk

Comment: no information was provided regarding the validation of the assessment instruments used

Filipovic 2006

Methods

Single‐blinded, parallel‐group RCT with 3 months treatment and follow‐up

Participants

Location: Serbia

Setting of recruitment and treatment: no information

Sample size:

  • Number randomised: 62 in intervention, 38 in comparison

  • Number completed: no information

Participant (baseline) characteristics:

  • Age: range 24 to 65

  • Gender: no information

  • Main diagnosis: asthma patients with bilateral nasal polyposis

  • Polyps status: 100% with polyps/no information

  • Previous sinus surgery status: no information

  • Previous courses of steroids: not reported

Other important effect modifiers, if applicable: all patients have asthma

Interventions

Intervention (n = 62): fluticasone propionate aqueous nasal spray, 200 µg once daily, for 3 months

Comparator group (n = 32): mometasone furoate aqueous nasal spray, 200 µg once daily, for 3 months

Use of additional interventions (common to both treatment arms): not reported

Outcomes

Outcomes of interest in the review:

Primary outcomes:

1. Disease severity symptom score, nasal symptoms score (postnasal drip, anterior rhinorrhoea, obstruction and loss of sense of smell), evaluated daily

Secondary outcomes:

Other outcomes reported by the study:

  • No information on other outcomes

Funding sources

"No information provided"

Declarations of interest

"No information provided"

Notes

Only an abstract was available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: no information, only published as an abstract. Unclear how randomisation was generated. Ratio does not seem 1:1.

Allocation concealment (selection bias)

Unclear risk

Comment: no information, only published as an abstract

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "single blind…"

Comment: unclear who was blinded and how blinding was maintained

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "single blind…"

Comment: unclear who was blinded and how blinding was maintained

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: no information on how many randomised versus completed

Selective reporting (reporting bias)

Unclear risk

Comment: no information, only published as an abstract

Other bias

Unclear risk

Comment: no mention of any validation of outcome measures. No information to assess whether baseline characteristics were balanced.

Holmberg 1997

Methods

3‐arm, double‐blind, parallel‐group RCT, with a 26‐week duration of treatment and 2 additional weeks of follow‐up

Participants

Location: Sweden, number of sites is unclear

Setting of recruitment and treatment: outpatient clinics

Sample size:

  • Number randomised: 19 in FP group, 18 in BDP group, 18 in placebo group

  • Number completed: 15 in FP group, 16 in BDP group, 11 in placebo group

Participant (baseline) characteristics:

  • Age mean (range): group FP: 54 (27 to 74); BDP group: 49 (26 to 68); placebo group: 47 (21 to 71)

  • Gender (M/F): FP group: 15/4; BDP group: 13/5; placebo group: 14/4

  • Main diagnosis: bilateral polyposis with a polyp score of 1 or 2

  • Polyps status: 100% with polyps

  • Previous sinus surgery status: 100% had history of at least 1 polypectomy within the previous 5 years

Other important effect modifiers:

  • Positive skin prick test (%): FP group: 3 (16%); BDP group: 6 (33%); placebo group: 5/18 (27%)

Inclusion criteria: bilateral polyposis with a polyp score of 1 or 2
Exclusion criteria: nasal polyposis with a score of 3 or 4 (or 0); concurrent nasal infection; an inability to cease treatment with systemic, inhaled or intranasal steroids or sodium cromoglycate on visit 1; had used antihistamines in the 48 hours prior to visit 1; had a contraindication to steroids or had any serious or unstable concurrent disease

Interventions

FP group (n = 19): fluticasone propionate, aqueous nasal spray, 2 actuations of 50 μg each to each nostril morning and evening (400 μg/day) for 26 weeks

BDP group (n = 18): beclomethasone dipropionate, aqueous nasal spray, 2 actuations of 50 μg each to each nostril morning and evening (400 μg/day) for 26 weeks

Placebo group (n = 18): placebo, actuations to each nostril morning and evening containing the same vehicle, as the interventions solutions including benzalkonium chloride as a preservative, for 26 weeks

Use of additional interventions (common to all treatment arms): a 4‐week run‐in period during which no treatment for polyposis, except for rescue loratadine, could be used by the patients

All patients were supplied with rescue loratadine tablets to use as relief medication, 10 mg loratadine once daily. Any use of rescue medication was documented on the patient's daily record card.

Outcomes

Outcomes of interest in the review:

Primary outcomes:

1. Patient‐reported disease severity, measured by daily records of all their nasal symptoms including: nasal blockage; sense of smell; sneezing and rhinorrhoea using a 4‐point rating system (0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 4 = severe symptoms)

2. Physician assessment of symptoms. No details were provided on how these were measured. Measured at 26 weeks.

3. Significant adverse effect: epistaxis

Secondary outcomes:

4. Polyp size by endoscopy (0‐ to 4‐point scale)

Other outcomes reported by the study:

5. Polyp score

6. Peak nasal inspiratory flow

7. Physician's assessment of change in symptoms

Funding sources

Glaxo Wellcome PLC, England and the Torsten and Ragnar Söderberg Foundation, Sweden

Declarations of interest

No conflicts of interest declared but 2 (of 6) authors had affiliations with Glaxo Wellcome Plc

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomized"

Comment: pg 271, col 1, para 3

No further details provided

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided in the paper

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "placebo: 2 actuations to each nostril morning and evening containing the same vehicle, as the fluticasone and beclomethasone solutions including benzalkonium chloride as a preservative. The placebo solution was therefore identical to the active treatments but did not contain any active drug."

Comment: pg 271, col 1, last para

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: no further information. Should also be low if there is adequate blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: 13/54 patients (24%) did not complete trial; 4/19 in fluticasone, 2/18 in beclomethasone, 7/18 (39%) in placebo group. Uneven drop‐out numbers: very high in placebo group.

Selective reporting (reporting bias)

High risk

Quote: "The primary efficacy endpoint was the physician's assessments of symptoms and polyp score on all clinic visits"

Comment: the methods section described assessment of polyps, and patient‐reported symptom scores. However, "physician assessment of outcomes and polyps score" were reported as primary outcomes in the results section. The results focused on "physician assessment of symptoms" and barely mention the results of the polyps (only "significant" for visit 5 on beclomethasone, not for fluticasone). In addition, there were some outcomes that seemed to have arbitrary, non‐predefined cut‐off points (% of days with symptom score < 2 in results). The denominator for the reported symptom scores outcome measures is not identified.

Other bias

High risk

Comment: primary outcome of physician assessment of outcomes was not well described in the paper with little information on the criteria used or any validation/inter‐rater reliability

Johansen 1993

Methods

3‐arm, "double‐blinded", multicentre, parallel‐group RCT, with a 3‐month duration of treatment and follow‐up

Participants

Location: 4 sites in Denmark, 1 site in Sweden

Setting of recruitment and treatment: unclear

Sample size:

  • Number randomised: 91 (numbers allocated to each group unknown)

  • Number completed: 86 (numbers allocated to each group unknown)

Participant (baseline) characteristics:

  • Age median (range): 52 (18 to 78)

  • Gender (M/F): 70/21

  • Main diagnosis: eosinophilic nasal polyposis with polyp scores of 2 or less on each side

  • Polyps status: 100% with polyps

  • Previous sinus surgery status: not provided in the paper

Other important effect modifiers:

  • 22 patients had asthma (allocation between groups unknown)

  • 8 patients were known to be acetylsalicylic acid (ASA) sensitive. (The ASA sensitive patients did not change their polyp score during treatment.)

Inclusion criteria: clinical diagnosis of eosinophilic nasal polyposis with polyp scores of 2 or less on each side. Eosinophilic polyposis was confirmed by nasal smear and/or biopsy.
Exclusion criteria:

  • Polyps surgically removed within 2 months

  • Neutrophilic polyposis

  • Systemic or topical nasal corticosteroid therapy within 2 months

Interventions

Group A (n = unknown): budesonide aqua (Rhinocort Aqua), 50 μg in each nostril x 2, twice daily (400 μg/day), 3 months

Group B (n = unknown): budesonide aerosol (Rhinocort Aerosol), 50 μg in each nostril x 2, twice daily (400 μg/day), 3 months

Group C (n = unknown): placebo (aqua or aerosol), unclear dose, 3 months

Use of additional interventions (common to all treatment arms): unclear ‐ no information was provided

Outcomes

Outcomes of interest in the review:

Primary outcomes:

1. Disease severity, measured weekly by patients. Symptoms included were nasal obstruction, sneezing and nasal secretions, recorded for each nasal cavity (scale 0 to 3).
Change in sense of smell was recorded at clinical visits using a scale of 0 to 3

2. Significant adverse effect: epistaxis

Secondary outcomes:

3. Other adverse effects: local irritation (including oral thrush, sore throat)

4. Polyp size (assessed using a 0 to 3 scale – definitions provided)

Other outcomes reported by the study:

  • Polyp size (assessed using a 0 to 3 scale – definitions provided)

  • Nasal and oral peak inspiratory flow

  • Nasal and oral peak expiratory flow

Funding sources

Astra Danmark A/S and Astra Draco AB, Sweden supported the study financially

Declarations of interest

No information provided

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "...randomised…"

Comment: mentioned in abstract but no further mention

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The patients were treated with either budesonide aqua (Rhinocort Aqua) or budesonide aerosol (Rhinocort Aerosol), 50 mcg x 2 in each nostril, twice daily = 400 mcg/day or placebo (aqua) or aerosol)"

Comment: whilst there may be adequate blinding for treatment versus placebo, there is no blinding when comparing different dosage forms

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no further information

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "Five patients withdrew from the study…"

Comment: no reasons given for withdrawals. Not included in any of the outcomes (including safety outcomes).

Selective reporting (reporting bias)

Unclear risk

Comment: all outcomes reported in the methods are mentioned in the results section, but numerical information for the results is not provided

Other bias

High risk

Comment: no comment on the validation of outcome measurements

The paper does not provide clear background characteristics for each group. The number randomised to each group was not provided.

Lund 1998

Methods

Double‐blind, parallel‐group RCT, with a 12‐week duration of treatment

Participants

Location: UK

Setting of recruitment and treatment: tertiary referral centre (Royal National ENT Hospital London)

Sample size:

  • Number randomised: 10 each in FP and BDP, 9 in placebo

  • Number completed: unclear, likely to be all

Participant (baseline) characteristics:

  • Age (mean, range): 52 (32 to 71), 46 (22 to 67) and 50 (27 to 69) in FP, BDP and placebo arms

  • Gender (M/F): 7/3, 9/1 and 7/2 in FP, BDP and placebo arms

  • Main diagnosis: "severe polyposis"

  • Polyps status: all had polyps, median total polyps score of 4 (both nostrils) using Lund‐Mackay CT score

  • Previous sinus surgery status: 66% had surgery (7/10 in FP and BDP arms, 5/9 in placebo)

  • 59% had condition for more than 10 years

  • All had allergy

Inclusion criteria:

Older than 16 years with a diagnosis of bilateral nasal polyposis requiring surgical interventions, meeting one or more of the following criteria:

  • a total polyp score of 4 or higher plus a CT scan score > 12;

  • a total polyp score of 3 or higher, a nasal blockage score of 2 or higher, plus a CT scan score > 12; and

  • a total polyp score of 2 or higher, a nasal blockage score of 2 or higher, a CT scan > 12, plus an UPSIT score > 32.

Exclusion criteria:

  • Concurrent purulent nasal infection

  • A requirement for more than 1000 μg beclomethasone (or equivalent) per day for the treatment of asthma

  • An inability to cease treatment with parenteral and intranasal corticosteroids or cromolyn sodium (sodium cromoglycate) at visit 1, used astemizole in the 6 weeks before the study or other antihistamines in the 48 hours before visit 1, or a contraindication to corticosteroid medications

Interventions

Intervention 1 (n = 10): fluticasone propionate aqueous nasal spray 400 µg per day, 2 actuations into each nostril morning and night

Intervention 2 (n = 10): beclomethasone dipropionate aqueous nasal spray 400 µg per day, 2 actuations into each nostril morning and night

Comparator (n = 9): placebo 2 sprays into each nostril twice a day

Use of additional interventions (common to both treatment arms): terfenadine 60 mg as rescue medicine

Outcomes

Outcomes of interest in the review:

Primary outcomes:

  • Disease severity ‐ collected patient diaries on a 0 to 4 scale for different symptoms, but only partially reported symptom‐free days

Secondary outcomes:

  • Adverse events – local irritation

  • Endoscopy – polyps size (scale not reported)

Other outcomes reported by the study:

  • PNIF, physician‐reported score for symptom severity

Funding sources

No information provided

Declarations of interest

No information provided, but 2 of the authors were employed by Glaxo Wellcome and reprint requests were addressed to Glaxo

Notes

Study had a 4‐week run‐in period

34 patients met criteria, 5 withdrew before randomisation (1 AE, 1 required polypectomy, 1 lack of efficacy, 2 did not return)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly allocated, using a computer‐generated random code and a block size of 6, to receive 1 of 3 treatments"

Comment: adequate sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "Patients were randomly allocated, using a computer‐generated random code and a block size of 6, to receive 1 of 3 treatments"

Comment: method not specified; blocked randomisation, but adequate blinding. Unclear if allocation concealment remained well maintained for this very small study.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The placebo was identical to the active formulations with the active ingredient omitted and was indistinguishable from the active treatments, which were themselves identical in appearance, taste, and smell."

Comment: there was a 4‐week pre‐treatment period where all patients were exposed to the placebo, but blinding should still be adequate

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: the same investigator did all the clinical assessments for all visits, but an identical placebo was used

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "last value carried forward technique" was used

Comment: drop‐outs not balanced, 3/10 in fluticasone propionate, 0/10 in beclomethasone and 4/9 in placebo

Selective reporting (reporting bias)

High risk

Comment: patient‐reported symptoms were collected (using diaries), but it was not specified how these were planned to be reported. Study only reported percentage of patients with 100% of days without nasal blockage, and the median % of days without nasal symptoms (different criteria). Other outcomes not reported at all.

There was also a higher percentage of patients in the fluticasone group (70%) compared to 33% and 30% in the beclomethasone and placebo groups, but details were not reported. Only stated that one of the adverse events in the FP group (throat irritation) was "predictable".

Other bias

High risk

Quote: "overall rhinitis symptoms (sneezing, rhinorrhoea, nasal itching)"

Comment: symptoms scores (by patients and clinicians) were used but no mention of validation. Some items seems to be single symptom (e.g. nasal blockage), but others seems to encompass a few things (e.g. "overall rhinitis symptoms")

Quote: "There was evidence, particularly from the acoustic rhinometric and PNIF data, that the patients randomly allocated to receive BDANS had milder symptoms than those randomly allocated to receive FPANS or placebo, even though all patients had been listed for surgical treatment on an equal basis before the study."

Comment: baseline symptoms and other assessment scores were not reported. Unable to judge for other aspects.

Penttila 2000

Methods

3‐arm, double‐blind, international, multicentre, parallel‐group RCT, with a 12‐week duration of treatment

Participants

Location: 12 centres in Denmark (3 centres), Finland (1 centre) and Sweden (1 centre)

Setting of recruitment and treatment: no information provided

Sample size:

  • Number randomised: 47 in 400 µg FPND twice daily, 48 in 400 µg FPND once daily, 47 in placebo

  • Number completed: 45 in 400 µg FPND twice daily, 47 in 400 µg FPND once daily, 41 in placebo

Participant (baseline) characteristics:

  • Age: mean 51 (range 22 to 83)

  • Gender: M/F; 107/35 (%M; 75.4%)

  • Main diagnosis: nasal polyposis

  • Polyps status: 100% with polyps

  • Previous sinus surgery status: 72% previous polypectomy (not within 3 months of trial)

Inclusion criteria: at least 16 years old, bilateral mild or moderate nasal polyposis
Exclusion criteria: severe polyposis (large polyps reaching below the lower edge of the inferior turbinate, causing total obstruction), concurrent purulent nasal infection, unable to cease treatment with intranasal steroids or sodium cromoglycate during run‐in period. Also excluded: people currently receiving inhaled corticosteroids or who had received depot or oral steroids within previous 3 months, patients who had received astemizole in 6 weeks prior to first clinic visit, patients who had undergone nasal polyp surgery in the previous 3 months, patients with hypersensitivity or contraindication to steroids, patients with allergic rhinitis or any other disease likely to interfere with outcomes, patients who were pregnant, lactating or likely to become pregnant during the study period.

Interventions

Intervention A (n = 47): fluticasone propionate nasal drops (FPND), 400 µg twice daily for 12 weeks

Intervention B (n = 48): fluticasone propionate nasal drops (FPND), 400 µg once daily for 12 weeks plus placebo drops once daily for 12 weeks

Comparator group C (n = 47): placebo nasal drops twice daily for 12 weeks

Process: contents were divided between both nostrils (200 µg per nostril) in the head down and forward position

Use of additional interventions (common to both treatment arms): all patients underwent a 2‐week run‐in period during which they ceased all medication for polyposis except loratadine tables for relief of troublesome symptoms (10 mg daily maximum)

Initial visit: physical and oropharyngeal examinations and details of clinical history

Initial and 12‐week visit: blood and urine samples

Outcomes

Outcomes of interest in the review:

Primary outcomes:

1. Disease severity, measured by assessing nasal blockage (0 to 3 scale) and overall rhinitis symptoms including sneezing, rhinorrhoea and nasal itching (0 to 3 scale) and sense of smell (0 to 3 scale) at 12 weeks after treatment

2. Significant adverse effect: epistaxis

Secondary outcomes:

3. Other adverse effects: local irritation

Other outcomes reported by the study:

Polyp size, degree of nasal blockage, overall rhinitis, peak nasal inspiratory flow (PNIF), olfactory function, rescue medication usage and adverse events

Funding sources

Funded by Glaxo Wellcome plc, UK

Declarations of interest

No information provided – but one of the authors worked at Glaxo Wellcome Research and Development

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "…double blind randomised treatment...", Figure 1, pg 95

Comment: no further information provided, but this is an "international, multicentre" study in 12 centres across 3 countries with regional monitors. Should have adequate sequence generation procedures.

Allocation concealment (selection bias)

Low risk

Quote: "…double blind randomised treatment...", Figure 1, pg 95

Comment: no further information provided. As above, allocation concealment should be adequate.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "active and placebo nasal drops were provided in identical single‐dose containers …"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: no further information provided. Should be adequate with use of adequate double‐blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "Sixteen patients were withdrawn during the randomized treatment phase, the majority due to lack of efficacy (five placebo, one FP 400 mg o.d., two FP 800 mg b.i.d.) or adverse events (five placebo, one FP 400 mg o.d., two FP 400 mg b.i.d.). One patient in the placebo group withdrew due to requirement for polypectomy. Two patients withdrew during the open phase, one requiring a polypectomy, the other for unspecified reasons", pg 97, column 2.

Comment: 16/142 (11.3%) withdrew; 10/47 placebo, 4/47 400 µg twice daily and 2/48 400 µg once daily did not complete the study. All these patients were included as the ITT population. Percentage in placebo group higher, but still quite small.

Selective reporting (reporting bias)

Unclear risk

Comment: all outcome measures in the methods section were discussed in the results section

Other bias

Unclear risk

Comment: no mention of validation of the symptom criteria used for the primary outcomes

Small 2005

Methods

3‐arm, double‐blind, multicentre, parallel‐group RCT, with a 4‐month duration of treatment and follow‐up

Participants

Location: 44 medical centres "worldwide"

Setting: no information

Sample size:

  • Number randomised: 122 in 400 µg, 115 in 200 µg, 117 in placebo group, respectively

  • Number completed: 109 in 400 µg, 101 in 200 µg, 95 in placebo group, respectively

Participant (baseline) characteristics:

  • Main diagnosis: bilateral nasal polyps and clinically significant congestion/obstruction

  • Age (mean): 400 µg: 48.3; 200 µg: 46.7; placebo: 47.5

  • Gender (%M/%F): 400 µg: 61/39; 200 µg: 66/34; placebo: 61/39

  • Polyps status: 100% with polyps

  • Previous sinus surgery status: no information

Other important effect modifiers:

  • Asthma history (%): 400 µg: 21; 200 µg: 18; placebo: 21

  • Perennial allergic rhinitis history (%): 400 µg: 25; 200 µg: 20; placebo: 17

Inclusion criteria:

  • ≥ 18 years with an endoscopically confirmed diagnosis of bilateral nasal polyps (at least 1 on a scale of 0 to 3) and clinically significant nasal congestion/obstruction (average morning score of 2 or higher on a scale of 0 to 3 for each of the last 7 days of the 14‐day run‐in period)

  • If had asthma, had a documented FEV1 ≥ 80% of the predicted value within the 6 months before screening and no asthma exacerbations within 30 days before screening. Those treated with inhaled corticosteroids were required to be on a moderate, stable regimen of beclomethasone dipropionate ≤ 800 mg/d or equivalent for 1 month before screening and to remain on a stable regimen throughout the study period.

Exclusion criteria:

  • Seasonal allergic rhinitis within the past 2 years

  • Sinus or nasal surgery within the previous 6 months or 3 nasal surgeries (or any surgical procedure preventing an accurate grading of polyps)

  • Presumed fibrotic nasal polyposis, or complete or near complete nasal obstruction

  • Nasal septal deviation requiring corrective surgery

  • Nasal septal perforation

  • Acute sinusitis, nasal infection or upper respiratory tract infection at screening or in the 2 weeks before screening

  • Ongoing rhinitis medicamentosa

  • Churg‐Strauss syndrome

  • Dyskinetic ciliary syndromes

  • Cystic fibrosis

  • Glaucoma or a history of posterior subcapsular cataracts; allergies to corticosteroids or aspirin, or any other clinically significant disease that would interfere with the evaluation of therapy

Interventions

400 µg group (n = 122): mometasone furoate nasal spray 200 μg twice daily (morning and evening) for 4 months

200 µg group (n = 115): mometasone furoate nasal spray 200 μg once daily (morning, matching placebo used in the evening) for 4 months

Placebo group (n = 117): placebo nasal spray twice daily (morning and evening) for 4 months

Use of additional interventions (common to both treatment arms): acetaminophen (paracetamol) was encouraged for analgesic purposes; NSAIDs limited to 5 consecutive days if alternative analgesia was required. Antibiotics were administered for bacterial infections at the discretion of the principal investigator.

Concomitant medications that would interfere with study evaluations were not permitted, including nasal sodium cromolyn; nasal atropine or ipratropium bromide; corticosteroids (except oral inhaled corticosteroids for asthma or mild‐strength or mid‐strength topical corticosteroids for dermatologic purposes); antihistamines; decongestants; topical, oral or ocular anti‐inflammatory drugs; or topical nasal or oral antifungal agents.

Outcomes

Outcomes of interest in the review:

Primary outcomes:

1. Disease severity, patient evaluation of symptoms (congestion/obstruction, loss of sense of smell, anterior rhinorrhoea and postnasal drip) measured daily on a diary card on a 4‐point scale (0 = none, 3 = severe)

2. Significant adverse effect: epistaxis (defined to include a wide range of bleeding episodes, from frank bleeding to bloody nasal discharge to flecks of blood in the mucus)

Secondary outcomes:

3. Other adverse effects: local irritation

Other outcomes reported by the study:

  • Polyps grade; bilateral score and proportion of patients demonstrating an improvement at endpoint

  • Therapeutic response (rated by investigator)

  • Peak nasal inspiratory flow

  • Treatment compliance

  • Number of withdrawals due to AE and events occurring in more than 2% of participants in any group

Funding sources

Supported by a grant from the Schering‐Plough Research Institute

Declarations of interest

The lead author received research support for POP1998 SAR study, PO1025 Polyps study, PPO2573 Follow up to Polyps study PO2683 Acute rhinosinusitis and PO2692 Acute rhinosinusitis study. The source of the grant was not stated.

2 of the authors were employed by Schering Plough; another author received a research grant from Schering Plough and other pharmaceutical companies.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "…randomised in a 1:1:1 ratio to 3 treatment arms…"

Comment: pg 1276, col 1, para 2. No further information. However, this is a relatively recent "international, multicentre" study in 44 centres worldwide. It should therefore have adequate sequence generation procedures.

Allocation concealment (selection bias)

Low risk

Comment: no information. However, this is a relatively recent "international, multicentre" study in 44 centres worldwide. It should therefore have adequate sequence generation procedures.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double blind, double dummy"; "… matching placebo nasal spray …"

Comment: pg 1276, col 1, para 1 and 2. "Matching placebo spray" mentioned and those on the 200 μg/day regimen were also given placebo nasal spray for the evening.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: no information. Likely to remain well blinded until end of study.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: 305/354 patients (86%) patients "completed 4‐month treatment period"

Comment: higher % of patients not completing in the placebo group 22/117 (19%); compared to the twice daily or once daily groups 13/122 (11%) and 14/114 (12%), respectively. Study mentioned analyses based on "all randomised subjects" using the "ITT principle" and endpoint was "defined as the last non‐missing reading for the subject" for bilateral polyps score; however, it is unlikely all were analysed as the numbers do not tally exactly with the "meta‐analysis subsequently reported"

Selective reporting (reporting bias)

Low risk

Comment: all outcomes reported in the methods section were reported in the results section

Other bias

Unclear risk

Comment: no information about the validation of outcome measures

Stjarne 2006

Methods

3‐arm, double‐blind, multicentre, parallel‐group RCT, with a 4‐month duration of treatment and follow‐up

Participants

Location: 24 centres in 17 countries worldwide

Setting: study conducted from 25 June 2001 to 20 January 2003

Sample size:

  • Number randomised: 102 in 400 µg, 102 in 200 µg, 106 in placebo group, respectively

  • Number completed: 93 in 400 µg, 94 in 200 µg, 87 in placebo group, respectively

Participant (baseline) characteristics:

  • Main diagnosis: bilateral nasal polyps and clinically significant congestion/obstruction

  • Age (mean): 400 µg: 47.6; 200 µg: 47.2; placebo: 50.9

  • Gender (%M/%F): 400 µg: 62/38; 200 µg: 70/30; placebo: 65/35

  • Polyps status: 100% with polyps

  • Previous sinus surgery status: not more than 3 times or within past 6 months

Other important effect modifiers:

  • Asthma history (%): 400 µg: 19; 200 µg: 15; placebo: 17

  • Perennial allergic rhinitis history (%): 400 µg: 18; 200 µg: 14; placebo: 22

Inclusion criteria:

  • ≥ 18 years with an endoscopically confirmed diagnosis of bilateral nasal polyps and clinically significant nasal congestion/obstruction (average morning score of 2 or higher on a scale of 0 to 3 for each of the last 7 days of the 14‐day run‐in period)

  • If had asthma, had a documented FEV1 ≥ 80% of the predicted value within the 6 months before screening and no asthma exacerbations within the 30 days before screening. Those treated with inhaled corticosteroids were required to be on a moderate, stable regimen of beclomethasone dipropionate ≤ 800 mg/d or equivalent for 1 month before screening and to remain on a stable regimen throughout the study period.

Exclusion criteria:

  • Seasonal allergic rhinitis within the past 2 years

  • Sinus or nasal surgery within the previous 6 months or 3 nasal surgeries (or any surgical procedure preventing an accurate grading of polyps)

  • Presumed fibrotic nasal polyposis, or complete or near complete nasal obstruction

  • Nasal septal deviation requiring corrective surgery or nasal septal perforation

  • Acute sinusitis, nasal infection or upper respiratory tract infection at screening or in the 2 weeks before screening

  • Ongoing rhinitis medicamentosa

  • Churg‐Strauss syndrome

  • Dyskinetic ciliary syndromes

  • Cystic fibrosis

  • Glaucoma or a history of posterior subcapsular cataracts

  • Allergies to corticosteroids or aspirin, or any other clinically significant disease that would interfere with the evaluation of therapy

Interventions

400 µg group (n = 102): mometasone furoate nasal spray 200 μg twice daily (morning and evening) for 4 months

200 µg group (n = 102): mometasone furoate nasal spray 200 μg once daily (morning, matching placebo used in the evening) for 4 months

Placebo group (n = 106): placebo nasal spray twice daily (morning and evening) for 4 months

Use of additional interventions (common to both treatment arms): acetaminophen (paracetamol) was encouraged for analgesic purposes; NSAIDs limited to 5 consecutive days if alternative analgesia was required. Antibiotics were administered for bacterial infections at the discretion of the principal investigator.

Concomitant medications that would interfere with study evaluations were not permitted, including nasal sodium cromolyn; nasal atropine or ipratropium bromide; corticosteroids (except oral inhaled corticosteroids for asthma or mild‐strength or mid‐strength topical corticosteroids for dermatologic purposes); antihistamines; decongestants; topical, oral, or ocular anti‐inflammatory drugs; or topical nasal or oral antifungal agents.

Outcomes

Outcomes of interest in the review:

Primary outcomes:

1. Disease severity, patient evaluation of symptoms (congestion/obstruction, loss of sense of smell, anterior rhinorrhoea and postnasal drip) measured daily on a diary card on a 4‐point scale (0 = none, 3 = severe)

2. Significant adverse effect: epistaxis (defined to include a wide range of bleeding episodes, from frank bleeding to bloody nasal discharge to flecks of blood in the mucus)

Secondary outcomes:

3. Other adverse effects: local irritation

Other outcomes reported by the study:

  • Polyps grade; bilateral score and proportion of patients demonstrating an improvement at endpoint

  • Therapeutic response (rated by investigator)

  • Peak nasal inspiratory flow

  • Treatment compliance

  • Number of withdrawals due to AE and events occurring in more than 2% of participants in any group

Funding sources

Supported by a grant from the Schering‐Plough Research Institute

Declarations of interest

"Schering Plough (manufacturer) was involved in the design and data analysis of this study and reviewed and approved this article"

Dr Stjarne received payment of "approximately $50 000 annually" from the manufacturer for a contribution to the Clarityn website. Dr Mosges was on the advisory board and Drs Staudinger and Danzig were employees of Schering‐Plough.

Notes

The study had a 14‐day, single‐blind run‐in period to exclude placebo responders and identify participants with stable disease.

The number of people screened/excluded after the run‐in period is not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was performed in blocks of 3 using random numbers generated by SAS function UNIFORM (SAS Institute, Cary, NC) with seed based on clock time. Randomization was stratified by the presence or absence of concurrent asthma."

Comment: computerised randomisation

Allocation concealment (selection bias)

Low risk

Comment: although randomisation was blocked, blinding should be adequate

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double blind"; "…matching placebo nasal spray …"

Comment: "Matching placebo spray" mentioned; dosing regimen the same across all groups

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: no information. Likely to remain well blinded until the end of the study.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "More than 85% of subjects completed the 4‐month treatment period, with more than twice as many placebo recipients as active drug recipients discontinuing during the treatment phase (18% vs 8%)."

Comment: drop‐out rates not balanced

Selective reporting (reporting bias)

Unclear risk

Comment: although all outcomes mentioned in the methods were reported, these were mostly not in sufficient detail (e.g. only P values)

Other bias

Unclear risk

Comment: no information about the validation of outcome measures

AE: adverse event
ASA: acetylsalicylic acid
BDP: beclomethasone dipropionate
CT: computerised tomography
d: day
F: female
FEV1: forced expiratory volume in one second
FP: fluticasone propionate
FPND: fluticasone propionate nasal drops
ITT: intention‐to‐treat
M: male
NSAIDs: non‐steroidal anti‐inflammatory drugs
PNIF: peak nasal inspiratory flow
RCT: randomised controlled trial
SD: standard deviation
UPSIT: University of Pennsylvania Smell Identification Test

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Bross‐Soriano 2004

POPULATION: all patients underwent endoscopic polypectomy at the start of the trial

Cannady 2005

STUDY DESIGN: not randomised

Dijkstra 2004

POPULATION: treatment started 1 week after FESS (continued for 1 year)

Filiaci 2000

DURATION: treatment and follow‐up only 8 weeks

Fowler 2002

DURATION: treatment and follow‐up only 8 weeks (study compared betamethasone nasal drops (dose unclear) versus 400 µg fluticasone propionate drops)

Giger 2003

POPULATION: allergic and non‐allergic rhinitis patients

Jankowski 2001

DURATION: treatment only 8 weeks

Keith 1995

DURATION: treatment only 1 month (budesonide: 800 µg versus 400 µg versus placebo)

Lildholdt 1995

DURATION: treatment and follow‐up only 4 weeks (budesonide: 400 µg versus 200 µg versus placebo)

NCT00788463

OTHER: trial registry entry for a clinical trial of "Beclomethasone aqueous spray and aerosol delivery systems in nasal polyps", registered in 2008. Contact with the study authors identified that this study was not completed and no results were published. The reason for termination was not provided.

NCT01405339

DURATION: treatment only 30 days. (Study compared 2 delivery methods for budesonide (mucosal atomisation device versus saline rinse bottle) in patients with CRSwNP)

NCT01623310

STUDY DESIGN: not a randomised study

Ongoing study evaluating the safety of intranasal administration of 400 μg of fluticasone propionate twice a day using a novel bi‐directional device in participants with chronic rhinosinusitis with or without nasal polyps

NCT02194062

POPULATION: this study looked at the impact of fluticasone spray versus budesonide respules on patients who just had FESS

Raghavan 2006

INTERVENTION: comparison of different head positions; treatment only 6 weeks

Reychler 2015

INTERVENTION: compared different doses (512 µg per day versus 2000 µg per day) and delivery methods of budesonide (nasal spray versus nebulisation). Also had an oral steroids group.

DURATION: treatment and follow‐up only 16 days

Singhal 2008

POPULATION: all patients had sinus surgery

Toft 1982

INTERVENTION: beclomethasone dipropionate 400 µg per day delivered as a nasal spray or through a "home‐made insufflator, consisting of a nose‐olive, a plastic tube and a funnel" to inhale powder from Rotacaps capsules meant for asthma treatment

Tos 1998

DURATION: treatment and follow‐up only 6 weeks

Wang 2012

DURATION: treatment only 1 week

CRSwNP: chronic rhinosinusitis with nasal polyps
FESS: functional endoscopic sinus surgery

Characteristics of studies awaiting assessment [ordered by study ID]

Bachert 2004

Methods

Participants

Interventions

Outcomes

Notes

Conference proceeding: we cannot locate the abstract

Meln 2004

Methods

Participants

Interventions

Outcomes

Notes

Conference proceeding: we cannot locate the abstract

Pisano 2000

Methods

Participants

Interventions

Outcomes

Notes

Conference proceeding: we cannot locate the abstract

Reim 2005

Methods

Participants

Interventions

Outcomes

Notes

We cannot locate the abstract

Characteristics of ongoing studies [ordered by study ID]

NCT01622569

Trial name or title

'Study evaluating the efficacy and safety of intranasal administration of 100, 200, and 400 μg of fluticasone propionate twice a day (bid) using a novel bi directional device in subjects with bilateral nasal polyposis followed by an 8‐week open‐label extension phase to assess safety'

Methods

Double‐blind, parallel assignment, randomised controlled trial

Participants

Adults with bilateral nasal polyposis

Interventions

  • Fluticasone propionate 100 μg twice a day

  • Fluticasone propionate 200 μg twice a day

  • Fluticasone propionate 400 μg twice a day

  • Matching placebo

For 16 weeks

Outcomes

  • Reduction of nasal congestion/obstruction symptoms

  • Reduction in total polyp grade (sum of scores from both nasal cavities)

No secondary outcomes were listed in the trial registry entry

Starting date

2013

Contact information

Optinose US Inc. No further details provided.

Notes

Study has been listed as completed on the registry website (October 2015). No results are currently available.

NCT01624662

Trial name or title

'Efficacy and safety study of intranasal administration of 100, 200, and 400 μg of fluticasone propionate twice a day (bid) using a novel bi directional device in subjects with bilateral nasal polyposis followed by an 8‐week open‐label extension phase to assess safety'

Methods

Double‐blind, parallel assignment, randomised controlled trial

Participants

Adults with bilateral nasal polyposis

Interventions

  • Fluticasone propionate 100 μg twice a day

  • Fluticasone propionate 200 μg twice a day

  • Fluticasone propionate 400 μg twice a day

  • Matching placebo

For 16 weeks

Outcomes

  • Reduction of nasal congestion/obstruction symptoms

  • Reduction in total polyp grade (sum of scores from both nasal cavities)

No secondary outcomes were listed in the trial registry entry

Starting date

2012

Contact information

Optinose US Inc. No further details provided.

Notes

Study has been listed as completed on the registry website (October 2015). No results are currently available.

NCT01946711

Trial name or title

'Buparid/PARI SINUS versus Budes® nasal spray in the therapy of chronic rhinosinusitis with polyposis nasi'

Methods

Open‐label, parallel assignment randomised controlled trial

Participants

Chronic rhinosinusitis with polyposis nasi in adult patients

Interventions

Budesonide inhalation versus budesonide spray

Outcomes

Change of inflammation of the nasal mucosa and paranasal sinus

Magnetic resonance imaging (thickness of mucosa, Lund‐Mackay score)

Safety assessment,

SNOT‐22 quality of life

Nasal obstruction

Endoscopic evaluation of nasal polyps

Starting date

2013

Contact information

Stefanie Prante ([email protected])

Notes

Also registered as EUCTR 2013‐002414‐12 on European Registry

Study authors were contacted and responded to say that the trial is due to be completed in 2016

Data and analyses

Open in table viewer
Comparison 1. High‐dose versus low‐dose intranasal corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3) Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3).

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3).

1.1 Average symptom score (3 domains)

1

237

Std. Mean Difference (IV, Random, 95% CI)

‐0.14 [‐0.39, 0.12]

1.2 Average symptom score (2 domains)

2

441

Std. Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.40, ‐0.03]

2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3) Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3).

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3).

2.1 Nasal blockage

2

441

Std. Mean Difference (IV, Random, 95% CI)

‐0.29 [‐0.47, ‐0.10]

2.2 Rhinorrhoea

2

441

Std. Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.34, 0.03]

2.3 Loss of sense of smell

1

237

Std. Mean Difference (IV, Random, 95% CI)

0.06 [‐0.20, 0.31]

3 Adverse effects: epistaxis Show forest plot

4

637

Risk Ratio (M‐H, Fixed, 95% CI)

2.06 [1.20, 3.54]

Analysis 1.3

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 3 Adverse effects: epistaxis.

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 3 Adverse effects: epistaxis.

4 Adverse effects: local irritation Show forest plot

3

542

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.28, 3.31]

Analysis 1.4

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 4 Adverse effects: local irritation.

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 4 Adverse effects: local irritation.

5 Nasal polyps size, measured as change from baseline (0 to 3 range scale) at 4 months Show forest plot

1

237

Mean Difference (IV, Fixed, 95% CI)

0.19 [‐0.16, 0.54]

Analysis 1.5

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 5 Nasal polyps size, measured as change from baseline (0 to 3 range scale) at 4 months.

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 5 Nasal polyps size, measured as change from baseline (0 to 3 range scale) at 4 months.

6 Nasal polyps ‐ proportion with improvement at 12 weeks Show forest plot

1

92

Risk Ratio (M‐H, Fixed, 95% CI)

1.71 [0.91, 3.21]

Analysis 1.6

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 6 Nasal polyps ‐ proportion with improvement at 12 weeks.

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 6 Nasal polyps ‐ proportion with improvement at 12 weeks.

Process for sifting search results and selecting studies for inclusion.
Figuras y tablas -
Figure 1

Process for sifting search results and selecting studies for inclusion.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 High‐dose versus low‐dose intranasal corticosteroids, outcome: 1.1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3).
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 High‐dose versus low‐dose intranasal corticosteroids, outcome: 1.1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3).

Forest plot of comparison: 1 High‐dose versus low‐dose intranasal corticosteroids, outcome: 1.2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3).
Figuras y tablas -
Figure 5

Forest plot of comparison: 1 High‐dose versus low‐dose intranasal corticosteroids, outcome: 1.2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3).

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3).
Figuras y tablas -
Analysis 1.1

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3).

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3).
Figuras y tablas -
Analysis 1.2

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3).

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 3 Adverse effects: epistaxis.
Figuras y tablas -
Analysis 1.3

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 3 Adverse effects: epistaxis.

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 4 Adverse effects: local irritation.
Figuras y tablas -
Analysis 1.4

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 4 Adverse effects: local irritation.

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 5 Nasal polyps size, measured as change from baseline (0 to 3 range scale) at 4 months.
Figuras y tablas -
Analysis 1.5

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 5 Nasal polyps size, measured as change from baseline (0 to 3 range scale) at 4 months.

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 6 Nasal polyps ‐ proportion with improvement at 12 weeks.
Figuras y tablas -
Analysis 1.6

Comparison 1 High‐dose versus low‐dose intranasal corticosteroids, Outcome 6 Nasal polyps ‐ proportion with improvement at 12 weeks.

Summary of findings for the main comparison. Different types of intranasal corticosteroid molecules for chronic rhinosinusitis

Different types of intranasal corticosteroid molecules for chronic rhinosinusitis

Patient or population: chronic rhinosinusitis (all studies recruited patients with bilateral polyps)
Setting: Europe/North America about 20 years ago, in secondary care settings
Intervention: fluticasone propionate
Comparison: beclomethasone dipropionate or mometasone furoate

Outcomes

№ of participants
(studies)

Relative effect (95%)

Anticipated absolute effects* (95% CI)

Quality

What happens

Low‐dose intranasal corticosteroids

High‐dose intranasal corticosteroids

Difference

Disease‐specific health‐related quality of life

Not measured

Impact unknown

Disease severity ‐ overall symptoms

  • Study 1: 37 participants

  • Study 2: 19 participants

  • Study 3: 100 participants

  • Study 1 (fluticasone propionate versus beclomethasone dipropionate): seemed to report results selectively, showing some benefits of fluticasone propionate for some symptoms

  • Study 2 (fluticasone propionate versus beclomethasone dipropionate): reported a "trend" towards less severity with fluticasone propionate compared to beclomethasone dipropionate

  • Study 3 (fluticasone propionate versus mometasone furoate): reported no statistically significant differences

⊕⊝⊝⊝
VERY LOW 1 2 3

No differences observed but evidence was too low quality to draw a conclusion

Adverse events: epistaxis

  • Study 1: 37 participants

  • Study 2: 19 participants

  • Study 3: 100 participants

  • Study 1 (fluticasone propionate versus beclomethasone dipropionate): 13/19 in fluticasone propionate group and 16/18 in beclomethasone dipropionate group had some form of adverse event, including epistaxis

  • Study 2 (fluticasone propionate versus beclomethasone dipropionate): 7/10 in fluticasone propionate group and 3/10 in beclomethasone dipropionate group had epistaxis

  • Study 3 (fluticasone propionate versus mometasone furoate): both drugs were "well tolerated"

⊕⊝⊝⊝
VERY LOW 1 2 3

Unclear whether the risk of epistaxis varies for different types of steroid molecules

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1Studies were either very small (n = 20 and n = 26) and had important drop‐outs or were only reported as an abstract with inadequate information available (n = 100). We considered all studies to be at unclear to high risk of selective reporting and attrition bias. The evidence was very low quality due to very serious imprecision and very serious risk of bias concerns.

Figuras y tablas -
Summary of findings for the main comparison. Different types of intranasal corticosteroid molecules for chronic rhinosinusitis
Summary of findings 2. High‐dose versus low‐dose intranasal corticosteroids for chronic rhinosinusitis

High‐dose versus low‐dose intranasal corticosteroids for chronic rhinosinusitis

Patient or population: chronic rhinosinusitis (all studies recruited patients with bilateral polyps)
Setting: studies mostly conducted in Europe/North America about 10 years ago, in secondary care settings
Intervention: high‐dose intranasal corticosteroids
Comparison: low‐dose intranasal corticosteroids

Outcomes

№ of participants
(studies)

Relative effect
(95% CI)

Anticipated absolute effects* (95% CI)

Quality

What happens

Low‐dose intranasal corticosteroids

High‐dose intranasal corticosteroids

Difference

Disease‐specific health‐related quality of life

Not measured

Impact unknown

Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months

All 4 EPOS domains

No information available

3 domains (nasal blockage, rhinorrhoea, loss of sense of smell) Range 0 to 3, lower score = less severe

№ of participants: 237
(1 RCT)

The mean disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3) ‐ average symptom score (3 domains) without high‐dose was

‐0.66 points

MD 0.13 points lower (0.37 lower to 0.11 more) than low‐dose group

⊕⊕⊝⊝
LOW 1 2 3

The average score for 3 types of symptoms seems to be similar between the high‐dose and low‐dose groups.

(2 domains: nasal blockage, rhinorrhoea)
Range 0 to 3, lower score = less severe

№ of participants: 441
(2 RCTs)

The mean disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3) ‐ average symptom score (2 domains) without high‐dose was

‐0.73 points

MD 0.19 points lower (0.36 lower to 0.02 lower) than low‐dose group

⊕⊕⊝⊝
LOW 1 2 3

The average score for 2 types of symptoms seems to be slightly lower for the high‐dose group. The clinical significance of this reduction is unclear.

Disease severity ‐ measured as average change from baseline at 4 months (range 0 to 3)

  • Nasal blockage (lower score = less severe)

№ of participants: 441
(2 RCTs)

The mean disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3) ‐ nasal blockage without high‐dose was

‐0.86 points

MD 0.24 points lower (0.39 lower to 0.08 lower) than low‐dose group

⊕⊕⊝⊝
LOW 1 2 3

The nasal blockage score seems to be slightly lower in the high‐dose group. The clinical significance of this reduction is unclear.

  • Rhinorrhoea (lower score = less severe)

№ of participants: 441

(2 RCTs)

The mean disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3) ‐ rhinorrhoea without high‐dose was

‐0.6 points

MD 0.15 points lower (0.33 lower to 0.03 higher) than low‐dose group

⊕⊕⊝⊝
LOW 1 2 3

The average score for rhinorrhoea seems to be similar between the high‐dose and low‐dose groups.

  • Loss of sense of smell (lower score = less severe)

№ of participants: 237
(1 RCT)

The mean disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3) ‐ loss of sense of smell without high‐dose was

‐0.6 points

MD 0.06 points higher (0.2 lower to 0.32 higher) than low‐dose group

⊕⊕⊝⊝
LOW 1 2 3

The average score for loss of sense of smell seems to be very similar between the high‐dose and low‐dose groups.

Adverse effects: epistaxis

№ of participants: 637
(4 RCTs)

RR 2.06
(1.20 to 3.54)

Study population

⊕⊕⊕⊝
MODERATE 4 5

The risk of epistaxis is likely to be higher in the higher‐dose groups. However, the studies included very minor nosebleeds, such as blood stains in the mucus, and most of these events are not likely to be severe.

57 per 1000

118 per 1000
(69 to 202)

61 more per 1000

(11 more to 145 more)

Moderate

60 per 1000

124 per 1000
(72 to 214)

64 more per 1000

(12 more to 153 more)

Adverse effects: local irritation

№ of participants: 542
(3 RCTs)

RR 0.97
(0.28 to 3.31)

Study population

⊕⊕⊝⊝
LOW 4 6 7

The risk of local irritation seems to be similar between groups, but the overall risks are underestimated due to the way the data were reported.

19 per 1000

18 per 1000
(5 to 62)

10 fewer per 1000

(13 fewer to 43 more)

Moderate

17 per 1000

17 per 1000
(5 to 58)

10 fewer per 1000

(13 fewer to 40 more)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; EPOS: European Position Paper on Rhinosinusitis and Nasal Polyps 2012;MD: mean difference; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1Scale validity, particularly discriminant validity (ability to distinguish the differences between groups), was unclear. There was a high risk of reporting bias. Studies tended to report enough information for meta‐analysis only for statistically significant results. One study, which had 101 participants, reported very similar values for both intervention arms for all disease scores but had no information related to SD.

2Small sample size ‐ evidence only from one or two relatively small studies.

3Only data from patients with bilateral nasal polyposis. We considered this to be indirectness of the evidence to patients without polyps but have not further downgraded the evidence.

4One of the studies had inadequate blinding ‐ a double dummy was not used to mask the twice daily (higher) versus once daily (lower) dose; the study had 101 participants.

5Sample size relatively small for a precise estimate of adverse events. We downgraded this outcome once, after taking into consideration the inadequate blinding in one of the studies and the relatively small sample size.

6Studies did not use consistent terminology/methods to report different types of local irritation. For analysis we only selected the most frequent types of local irritation from a list (to avoid double counting). This is a possible underestimation of overall event rates. The relatively low event rates and small sample size contributed to the large confidence intervals.

Figuras y tablas -
Summary of findings 2. High‐dose versus low‐dose intranasal corticosteroids for chronic rhinosinusitis
Comparison 1. High‐dose versus low‐dose intranasal corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Disease severity ‐ overall symptoms, measured as average change from baseline at 4 months (range 0 to 3) Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 Average symptom score (3 domains)

1

237

Std. Mean Difference (IV, Random, 95% CI)

‐0.14 [‐0.39, 0.12]

1.2 Average symptom score (2 domains)

2

441

Std. Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.40, ‐0.03]

2 Disease severity ‐ individual symptoms, measured as average change from baseline at 4 months (range 0 to 3) Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

2.1 Nasal blockage

2

441

Std. Mean Difference (IV, Random, 95% CI)

‐0.29 [‐0.47, ‐0.10]

2.2 Rhinorrhoea

2

441

Std. Mean Difference (IV, Random, 95% CI)

‐0.15 [‐0.34, 0.03]

2.3 Loss of sense of smell

1

237

Std. Mean Difference (IV, Random, 95% CI)

0.06 [‐0.20, 0.31]

3 Adverse effects: epistaxis Show forest plot

4

637

Risk Ratio (M‐H, Fixed, 95% CI)

2.06 [1.20, 3.54]

4 Adverse effects: local irritation Show forest plot

3

542

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.28, 3.31]

5 Nasal polyps size, measured as change from baseline (0 to 3 range scale) at 4 months Show forest plot

1

237

Mean Difference (IV, Fixed, 95% CI)

0.19 [‐0.16, 0.54]

6 Nasal polyps ‐ proportion with improvement at 12 weeks Show forest plot

1

92

Risk Ratio (M‐H, Fixed, 95% CI)

1.71 [0.91, 3.21]

Figuras y tablas -
Comparison 1. High‐dose versus low‐dose intranasal corticosteroids