Disclosure Consultant for IntersectENT Minor Stockholder Off label - PDF document

STEROIDS AND STENTS Pacific Rim Otolaryngology Update February 16, 2013 Andrew H. Murr, MD FACS Professor and Interim Chairman Roger Boles, MD Endowed Chair in Otolaryngology Education Department of Otolaryngology-Head and Neck Surgery University of California, San Francisco School of Medicine Chief of Service Otolaryngology-Head and Neck Surgery San Francisco General Hospital Disclosure • Consultant for IntersectENT – Minor Stockholder • Off label discussion – Fluticasone – Budesonide • Many members of the rhinology community have contributed to the stent technology that I will discuss: Team Effort!

Treatment of Nasal Polyps • Antibiotics • Antifungals • Corticosteroids • Anti-Leukotrienes • Antihistamines • Mast cell stabilizers • Parasympathetic blockade drugs • Surgery Corticosteroid Delivery: What is the Evidence? • Topical – Spray – Irrigation • Systemic • Direct injection

Evidence:Topical Delivery Joe SA, Thambi R, Huang J. A systematic review of the use of intranasal steroids in the treatment of chronic rhinosinusitis. Otolaryngol Head Neck Surg. 2008 Sep;139(3):340-7. Review. PubMed PMID: 18722209. • “Th • “This systematic review showed that revi intranasal steroids intra decr decrease polyp size, which we believe whic would provide some wou relief of nasal relie obstruction.” obst Evidence: Topical Steroids Larger Dose [100 micrograms] Jankowski R, Klossek JM, Attali V, Coste A, Serrano E. Long-term study of fluticasone propionate aqueous nasal spray in acute and maintenance therapy of nasal polyposis. Allergy. 2009 Jun;64(6):944-50. Epub 2009 Mar 3. PMID: 19298572 .

Evidence: Topical Steroids Larger Dose [100 micrograms] Jankowski R, Klossek JM, Attali V, Coste A, Serrano E. Long-term study of fluticasone propionate aqueous nasal spray in acute and maintenance therapy of nasal polyposis. Allergy. 2009 Jun;64(6):944-50. Epub 2009 Mar 3. PMID:19298572. Evidence: Budesonide (Pulmicort) Respules Kanowitz SJ, Batra PS, Citardi MJ. Topical budesonide via mucosal atomization device in refractory postoperative chronic rhinosinusitis. Otolaryngol Head Neck Surg. 2008 Jul;139(1):131-6. PubMed PMID: 18585575.

Evidence: Budesonide (Pulmicort) Respules Kanowitz SJ, Batra PS, Citardi MJ. Topical budesonide via mucosal atomization device in refractory postoperative chronic rhinosinusitis. Otolaryngol Head Neck Surg. 2008 Jul;139(1):131-6. PubMed PMID: 18585575. Does Budesonide in Respule Nasal Washes cause Adrenal Cortex Suppression? Sachanandani NS, Piccirillo JF, Kramper MA, Thawley SE, Vlahiotis A. The effect of nasally administered budesonide respules on adrenal cortex function in patients with chronic rhinosinusitis. Arch Otolaryngol Head Neck Surg. 2009 Mar;135(3):303-7. PubMed PMID: 19289711.

Systemic Steroid Delivery • Cochrane Database 2011 Jul6;(7):CD005232 • “The authors found three randomised controlled trials [166 patients], albeit of moderate to poor quality, that suggest a short-term benefit of oral steroids in patients with multiple nasal polyps. To address the issue more thoroughly well- designed, prospective, randomised controlled trials are still needed.” • Parameters: – Polyp size (endoscopic) – Symptom questionnaires – QOL Bioabsorbable Steroid Eluting Stent

Causes of FESS Failure • Recurrent inflammation • Recurrent polyps • Adhesion/synechiae formation • Middle turbinate lateralization • Stenosis of surgically MT created ostia Septum Bioabsorbable Steroid-Eluting Stent Device FDA Approval: August, 2011 FDA Approval for mini stent: December, 2012 • Stent – Spring-like design – Polylactide-co-glycolide • Mometasone Furoate – Gradually released over approximately 30 days – 370 micrograms – FDA approved – Spray • 100 micrograms/day A.R. • 200 micrograms/day Polyps

Example of Stent Placement International Forum of Allergy & Rhinology Vol. 1 No.1 January/February 2011 • Prospective, multi-center, randomized, double blind, controlled clinical trial – Patients undergoing FESS for CRS refractory to medical management of 3 months duration or more – With or without Nasal Polyps – Primary or revision surgery – Intra-patient control design – Oral steroids not permitted in a 14 day run-in – IV steroids given perioperatively • 4mg – 20 mg – No post operative steroids until Day 30 – 14 Day course of Amoxicillin with Clavulonic Acid begun one day preoperatively – Saline spray permitted throughout

Follow-up Paradigm • POD – 7 – 14 – 21 – 30 • Steroid prescription allowed at this juncture if necessary by clinical opinion of treating physician – 45 – 60 Efficacy Assessment Form

SAFETY • No evidence of systemic steroid absorption • No evidence of adrenal-pituitary axis suppression INFLAMMATION: • Day 21 p = .0032 • Day 30 p = .0011 • Day 45 p = .0022

Bioabsorbability Polyp/Inflammation Assessment

Polypoid Change, Adhesion, Middle Turbinate Position How the Coated Stent Works… • Function of the Stent – Mechanical function • Spring like mechanical function • Placement of drug in key location • Patency of ethmoid cavity – Pharmacological function • Systemic steroid side effects obviated • Decreased polyp formation and inflammation • Improves mechanical function of stent – Adhesions/stenosis – Bioabsorbable • Li, Downie, Hwang, AJR, 2009;23:591-596 PMID 19958608

Benefit of Steroid Elution: Historical Comparison • Current Stent Study: – Adhesion rate with steroid: 5.3% – Adhesion rate without steroid: 21.1% – P=0.0313 • Historical Comparison: – Wormald et al., AJR, 2006 Jan-Feb; 20(1):7-10 PMID 16539287 • Hyaluronic Acid (HA) Packs to No packing • HA adhesion rate 21% – Miller and Steward, Oto-HNS, 2003;128:862-869 PMID 12825038 • HA to non absorbable packing: 35% overall with adhesions, each group similar (~25%) • 19% required surgical (in office) intervention

• 120 videos – 14,30,45 days post FESS • Comparison b/t onsite raters and the panel: strong agreement Categoric variables : • MT position – Kappa = .499, prevalence index =0.925 • Adhesions – Kappa=.364, prevalence index=0.829 Continuous variables : • Inflammation – Reliability coefficient=0.554 • Crusting – Reliability coefficient=0.620 Bland-Altman Plots Smith et. al., Laryngoscope, 122:230-236, January 2012 • The results suggest that the endoscopic scoring parameters have acceptable interexaminer reproducibility for both categoric and continuous data elements and that parameters are suitable for evaluating the middle meatal and ethmoid sinus anatomy in postsurgical patients. • Green Line: 95% agreement b/t real time and panel • Red Line: mean difference b/t on site and panel scores

Expanded Clinical Data: Advance II Marple BF, Smith TL, Han JK, Gould AR, Jampel HD, Stambaugh JW, Mugglin AS. Advance II: A Prospective, Randomized Study Assessing Safety and Efficacy of Bioabsorbable Steroid-Releasing Sinus Implants. Otolaryngol Head Neck Surg. 2012 Jun;146(6):1004-11. Epub 2012 Feb 1. PubMed PMID: 22301107. • 105 Patients • Intra-patient control design • Panel raters and on- site raters Intervention

POST-OPERATIVE INTERVENTION Steroid Prescription or Surgical Adhesion Lysis Figure 4. Frequency of postoperative interventions by treatment group at day 30, as judged by the independent panel and in real time by on-site clinical investigators. Postoperative intervention is a composite of either surgical adhesion intervention and/or oral steroid intervention. Arrows with percentages indicate relative reductions. 3 Prospective Clinical Trials Studied in > 200 patients Pilot ADVANCE ADVANCE II Study 1 Study 2 Pivotal Trial 3 n=38 n=50 n=105 4 sites 7 sites 11 sites Randomized Non-Randomized Randomized Controlled Single Arm Controlled Double Blind Safety / Symptoms Double Blind Intra-patient Control to 6 months Intra-patient Control Broad Patient Populations • > 60% polyps at baseline • > 30% prior sinus/nasal surgery • > 12 Mean Lund-Mackay CT stage 1. Murr AH, Smith TL, Hwang PH, et al. Int Forum Allergy Rhinol. 2011;1:23–32. 2. Forwith KD, Chandra RK, Yun PT, Miller SK, Jampel HD. Laryngoscope . 2011;121:2473–2480. 3. Marple BF, Smith TL, Han JK et al. Otolaryngol Head Neck Surg. 2012; 146(6) 1004–1011.

PubMed PMID: 22550039 . Meta Analysis: 2 Double Blind, Randomized Controlled Trials • 143 patients • Bioabsorbable Steroid Eluting Stent: Improves post-op healing • Reduction in need for oral steroids & surgical adhesion lysis PMID: 22550039 Relative p value Reduction Need for Medical / Surgical 35% 0.0008 Tx Need for Oral Steroids 40% 0.0023 Polyposis 46% <0.0001 Panel grading

Propel: Bioabsorbable Steroid Eluting Stent • LEVEL 1A EVIDENCE • Reduction in: – adhesions – polyposis – inflammation – middle turbinate lateralization – oral steroid Rx and surgical adhesion lysis FUTURE DEVELOPMENT • 1. OFFICE BASED PRODUCT • 2. OTHER SINUSES – FRONTAL • 3. DRUGS

Conclusion • Sinusitis is an inflammatory disease and steroids can be effective • Novel methods of steroid delivery have promise for treatment effectiveness and for decreased morbidity