Evaluation of a steroid releasing sinus implant for the treatment of patients undergoing frontal sinus surgery for chronic rhinosinusitis

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1 Expert Review of Medical Devices ISSN: (Print) (Online) Journal homepage: Evaluation of a steroid releasing sinus implant for the treatment of patients undergoing frontal sinus surgery for chronic rhinosinusitis Sean Bury & Ameet Singh To cite this article: Sean Bury & Ameet Singh (2017) Evaluation of a steroid releasing sinus implant for the treatment of patients undergoing frontal sinus surgery for chronic rhinosinusitis, Expert Review of Medical Devices, 14:2, , DOI: / To link to this article: Accepted author version posted online: 16 Jan Published online: 05 Feb Submit your article to this journal Article views: 4 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [ ] Date: 06 February 2017, At: 10:13

2 EXPERT REVIEW OF MEDICAL DEVICES, 2017 VOL. 14, NO. 2, DEVICE PROFILE Evaluation of a steroid releasing sinus implant for the treatment of patients undergoing frontal sinus surgery for chronic rhinosinusitis Sean Bury and Ameet Singh Division of Otolaryngology, George Washington University, Washington, DC, USA ABSTRACT Introduction: Management of the frontal sinus places great demands on the otolaryngologist. Given that the fronto-ethmoidal region is susceptible to recurrent inflammation, scarring, and stenosis, maintaining long-term patency of the frontal sinus is a difficult challenge. Oral and topical antiinflammatory therapy, post-operative stenting, and home-brew drug elution have been used for the treatment of the frontal sinus with mixed success. Recently an implant has been approved for postoperative placement into the frontal recess. This implant provides reliable and consistent steroid drug elution to address inflammation of the frontal recess secondary to chronic sinusitis. Areas covered: This review discusses the development and application of steroid eluting implants in the postoperative care of patients with chronic frontal sinusitis. All randomized controlled trials evaluating steroid eluting implants are discussed. Relevant supporting material discussing background, economics, safety are included. Expert commentary: Steroid eluting implants fulfill a unique niche in the treatment following frontal sinus surgery. They are shown to decrease the need for post-operative interventions and improve outcomes in patients with chronic sinusitis. There is significant potential for growth in the use of steroid eluting implants. ARTICLE HISTORY Received 9 November 2016 Accepted 10 January 2017 KEYWORDS Chronic frontal sinusitis; frontal recess; steroid-eluting implant; steroid stent; mometasone furoate 1. Introduction 1.1. Incidence of chronic rhinosinusitis, functional endoscopic sinus surgery, and frontal sinus surgery Chronic rhinosinusitis (CRS) is a widespread disease entity in the US population with data showing 6 16% of the population affected [1]. The wide range in its incidence is due to differences in inclusion criteria across studies nevertheless the disease is highly prevalent. In 2011, 29.6 million people were diagnosed with CRS, although this number was based on reported clinical symptoms, and not necessarily corroborated by imaging or nasal endoscopy. The surgical treatment of CRS is growing rapidly (see table 1). Approximately 257,000 paranasal sinus procedures, including balloon sinuplasties, were performed in 2006, compared to nearly 800,000 procedures performed in 2014 [2]. A significant number of these surgical interventions addressed the frontal sinus. Medicare national billing summary data showed that 23% of sinus procedures from 2003 to 2011 involved the frontal sinus. Furthermore, there has been an upward trend in frontal sinus procedures, as the number of endoscopic frontal sinus procedures performed has almost doubled in the interval from 2000 to 2011 [3]. This trend likely indicates increased recognition of frontal sinus contribution to sinus disease combined with introduction of new surgical treatments such as balloon sinus dilatation Surgical management of frontal sinus disease The surgical management of the frontal sinus is fraught with intraoperative and postoperative challenges. Greater anatomical complexity, need for specialized instrumentation/equipment, and greater risk of complications make frontal sinus surgery uniquely challenging. Postoperatively, persistent inflammation of the frontal recess can lead to scarring and long-term stenosis with clinical sequelae. Common medical therapies have included oral and topical steroids, saline irrigations, and oral and topical antibiotics. Nonabsorbable materials such as stents have been utilized to maintain postoperative patency of the frontal recess. Balloon devices have been used intraoperatively and postoperatively to maintain frontal sinus patency. The most recent development in treatment is approval of a steroid-eluting implant for the frontal sinus opening. 2. Overview of the market Steroid-eluting implants have a unique role in the market for the treatment of CRS. Although antibiotics, steroids (oral and topical) have been utilized for the treatment of chronic frontal sinusitis, their efficacy is somewhat limited. In addition, the potent long-term side effects of oral steroids are well documented. Their frequent and long-term utilization for the treatment of chronic frontal sinusitis may result in serious and harmful side effects for the patient. CONTACT Ameet Singh asingh@mfa.gwu.edu 2017 Informa UK Limited, trading as Taylor & Francis Group

3 94 S. BURY AND A. SINGH Table 1. Timeline of advances in endoscopic sinus surgery technology. 1. FESS introduced to United States 1. Balloon sinus dilation approved in United States 1. Pilot study for PROPEL stent in ethmoidal sinus 1. ADVANCE II study for PROPEL stent in ethmoidal sinus 2. ADVANCE study for PROPEL stent in ethmoidal sinus 2. PROPEL mini stent approved for ethmoidal sinus 3. PROPEL stent approved for ethmoidal sinus PROGRESS study for PROPEL mini in frontal sinus 2. PROPEL mini stent approved for frontal sinus 2.1. Topical treatments of CRS Topical nasal treatments include nasal saline and topical steroids. Nasal saline provides symptomatic relief in children and adults suffering from CRS with or without nasal polyps but is less effective than nasal steroids [4,5]. Topical nasal steroids are the mainstay of relief of CRS symptoms. They provide antiinflammatory relief without systemic side effects. They have been shown to improve symptoms in adults with CRS [6]. Furthermore, intranasal mometasone furoate (MF) has been shown to reduce polyp formation, in addition to reducing symptoms [7]. Unfortunately, due to the anatomical location of the frontal sinus, most steroid drug-delivery systems do not successfully reach the frontal sinus [8]. This is especially problematic, as steroid sprays are the standard of care after functional endoscopic sinus surgery (FESS) [9]. To address this anatomical constraint, a variety of patient positions have been employed. Beule et al. advocated sinonasal irrigation in a vertex-to-floor position to ensure irrigation of the frontal sinus. Unfortunately, patient fitness, especially in the elderly, may limit this. For those unable to perform vertex to floor, an alternate head-to-sink position was found to allow some irrigation of the frontal sinus [10]. Habib et al. further investigated the effects of position on the delivery of atomized nasal steroids to the frontal sinus. It was found that the lying head back position was more effective than head-to-floor position [11]. However, this investigation was performed on cadavers, and the positions have not been demonstrated effective across larger populations [12] Oral treatments of CRS Oral steroids are some of the most effective, available, and cost-effective anti-inflammatory agents that have shown benefit in patients with nasal polyps undergoing sinus surgery [13]. Unfortunately, systemic side effects limit their use [9]. Long-term side effects include avascular necrosis of the hip, cataracts, and weight gain. Short-term effects include mood changes, poor blood sugar control, GI upset, and insomnia. These side effects contribute to growing health-care costs and patient morbidity [14,15]. Oral antibiotics have a limited role in the treatment of chronic sinusitis. Although oral antibiotics have been recommended for acute exacerbations of chronic sinusitis, long-term treatment with systemic antibiotics is rarely associated with enduring improvement in symptoms in adults with CRS [9]. Only long-term use of macrolides has shown some symptomatic improvement in patients with chronic sinusitis [16]. Recent evidence suggests that frequent use of antibiotics may significantly alter the paranasal sinus microbiome [17]. Additionally, systematic review does not demonstrate improvement in signs and symptoms of CRS with topical antibiotics [11] Market niche Topical treatments, oral steroids, and antibiotics have been employed in various combinations in an effort to reach optimal care for individual CRS patients. While this is adequate for some, there are many patients that are refractory to such treatments. Surgery is indicated for CRS patients who have failed maximal medical therapy. Postoperatively, patients often undergo extensive medical regimens to maintain outcomes following sinus procedures. With the current emphasis on health-care value, there has been a focused search for more cost-efficient and effective treatment options to maintain frontal sinus surgical results. Currently, the steroid-eluting implant is the only US FDA approved technology shown to improve outcomes following frontal sinus surgery. 3. Introduction to the device The PROPEL mini is an expandable, dissolvable polymer (polyactide-co-glycolide) coated with steroid (mometasone fuorate) that conforms to the patient s ethmoid sinus or frontal recess. The implant delivers a sustained release of 370 µg MF over 30 days. It is the miniature version of the PROPEL implant, a similarly constructed device that delivers the same amount of MF [18 21] Comparison of PROPEL and PROPEL mini The PROPEL mini implant has a 4.0-mm compressed diameter and 16.0-mm profile. The PROPEL stent has a 5.2-mm compressed diameter and 23.0-mm profile (see figure 1). The PROPEL mini implant was approved 1 year after the PROPEL implant (2011 and 2012, respectively) and originally had a similar indication as the PROPEL implant (approved August 2011): deployment in patients 18 years of age following ethmoid sinus surgery to maintain patency of the ethmoid sinus. Due to its smaller size, investigators postulated that the PROPEL mini would be beneficial in maintaining the patency of the frontal sinus following frontal sinus surgery. In March 2016, the PROPEL mini was approved for use in the frontal sinus following frontal sinus surgery based on the data from the PROGRESS study [22].

4 EXPERT REVIEW OF MEDICAL DEVICES 95 Figure 1. Demonstrates profile comparison PROPEL steroid-releasing (or drugeluting) implant and PROPEL Mini steroid-releasing (or drug-eluting) implant. Reproduced with permission from Intersect ENT Device construction The PROPEL mini consists of three components: a polymer scaffolding, a polyethylene glycol coating, and MF embedded in the coating. The polymer scaffolding is polyactide-co-glycolide, an inert monofilament that is woven into a lattice spread. Layered onto the monofilament is a drug-eluting formulation of polyethylene glycol, and the active ingredient, MF. Polyethylene glycol helps regulate the release of MF and also has minor anti-inflammatory properties. A volume of 370 µg of MF is embedded in the polyethylene glycol and released in a controlled fashion as the implant dissolves. Peak concentrations are attained at 7-13 days post implant, with > 90% of the steroid released by 13 days. MF is detected in nasal tissue up to 60 days postimplantation 1 [23] Implantation Prior to delivery, the PROPEL mini is compressed in a 110-mm delivery sheath that is curved to allow endonasal access into the ethmoid sinus or the frontal sinus recess. The implant is then deployed via a syringe-like mechanism (see figure 2), and after delivery, the device expands to fit the contours of the site. Accurate delivery is ensured with endoscopic visualization. 4. Cost-effectiveness The cost-effectiveness of the steroid-eluting implants following sinus surgery has been evaluated in two studies. These studies assessed the impact of the PROPEL implant following ethmoidal sinus surgery. PROPEL mini following frontal sinus surgery has not had sufficient time in the market for assessment of post-marketing cost-effectiveness. Although placement of the PROPEL mini following frontal sinus surgery uses a different CPT code and the device has a separate NDC Figure 2. Demonstrates delivery device for PROPEL Mini steroid-releasing (or drug-eluting) implant. Reproduced with permission from Intersect ENT. coding number, the data from two independent studies suggest that steroid-eluting implants are cost-effective Cost-effectiveness of PROPEL implant from third-party payer perspective Rudmik and Smith aimed to evaluate the cost-effectiveness of a mometasone steroid-eluting sinus implant compared to a nonsteroid-eluting sinus implant following ethmoidal endoscopic sinus surgery for CRS from a third-party payer perspective [24]. Data from steroid-eluting stent randomized controlled trials were used to measure the cost-effectiveness at willingness-to-pay (WTP) thresholds 1 of $10,000, $25,000, and $50,000. To assess this, a decision tree based on postoperative interventions was developed. The probability of postoperative interventions occurring was calculated from pooling of Murr et al., Advance and Advance II studies. It was demonstrated with 74.3% certainty that steroid-eluting implants are costeffective at $10,000 WTP threshold, 87.2% certainty at $25,000, and 90.5% certainty at $50,000 WTP with 60-day postoperative end point. This indicates that if a payor is willing to pay 10, 25 or 50k per QALY improvement, then the certainty that the implants are cost-effective rises from 74.3% to 87.2% to 90.5%, respectively Budget impact of PROPEL implant In a separate study, Rizzo et al. further delineated the economic effectiveness of steroid-eluting implants [25]. In this study, an Excel-based model was used to evaluate the budget impact of PROPEL implant placement post-fess from a selfinsured employer and third-party payer perspective. Budget impact was defined as the difference in resource utilization between a population who had implant placement in

5 96 S. BURY AND A. SINGH endoscopic sinus surgery and a population who did not have implant placement following endoscopic sinus surgery. Resource utilization was calculated from the average cost on the probability of three events: (1) severe adhesion/synechiae requiring a lysis procedure, (2) recurrent polyposis requiring a 2- week rescue course of oral corticosteroids, and (3) revision sinus surgery within 6 months post-op and included a fourth variable that was not a probability: the cost of implant and average cost of nasal packing and spacers in FESS. These variables were input in three scenarios in two settings: (1) US self-insured employer health plan with 1.5 million people and (2) the health-care budget of a US third-party payer. The scenarios envisioned a patient population receiving PROPEL implants for refractory CRS who were followed over a 2 and 6-month postoperative period. A third scenario limited the population to CRS patients with nasal polyps undergoing refractory sinus surgery. These scenarios demonstrated that the PROPEL implant, in general, saved a small amount of money for self-insured employer and had a minimal increase in cost for US third-party payer. The PROPEL stent resulted in savings of $0.003 per member per month over a 6- month period and increase in cost of $0.07 per member per month over a 2-month period for a self-insured employer. For third-party payer, an increase of $0.08 per member per month for a 2-month period and an increase $0.036 for 6-month period. For subgroup of patients with nasal polyps followed over a 6-month period, there was an estimated $0.001 savings per member per month for selfinsured employer and an increase of $0.011 for commercial payer Summary of cost-effectiveness Both studies demonstrated an economic effectiveness of steroid-eluting stent at 60 days post-surgery. Lack of long-term data prevented assessment of effectiveness at greater than 60 days, but the trend shows increasing effectiveness at long-time intervals. As more data becomes available, longterm economic models can be created. Additionally, further studies may more clearly demonstrate economic effectiveness on subgroups of CRS patients, such as those with nasal polyposis or recalcitrant CRS patients. followed an intra-patient study design in which a steroid-eluting implant was inserted into either the right or left middle meatus, and the contralateral side received a nondrug eluting implant. In Group 2 (n = 5), patients received bilateral drugeluting implants to assess the potential for systemic toxicity. Patients had regularly scheduled follow-up at 1 week intervals for the first 4 weeks, with subsequent follow-up at 6 and 8 weeks during which endoscopic assessments were performed. With this method of assessment, ethmoid sinus inflammation was noted to be consistently lower over 6 weeks on the implanted side. There was statistically significantly less polypoid change, adhesion, and lateralization of the middle turbinate up to 30 days postoperatively. Furthermore, the study revealed that the PROPEL implant had dissolved 70% by 3 weeks, with complete dissolution by 45 days ADVANCE trial The second study validating the PROPEL implant was the ADVANCE trial by Forwith et al. ADVANCE was a prospective multicenter trial that evaluated 50 patients with chronic ethmoidal sinusitis [19]. Forty patients underwent bilateral implant placement in the ethmoid sinus, and 10 patients with unilateral disease had unilateral implant placement. Endoscopic follow-up was performed at 7, 14, 21, 30, and 60 days. Sinus inflammation showed a linear decrease in severity. The implant degraded as predicted with 10 20% of implant remaining after 30 days and complete dissolution by 60 days. ADVANCE also sought to address questions of potential for ocular risk associated of steroid-eluting implants. No clinically significant changes from baseline in intraocular pressures nor lens opacities were observed. A qualitative quality-of-life outcomes survey, the SNOT-22, demonstrated a decrease in score from an average of 3 to 1 over the first 30 days, with scores remaining at an average of 1 6 months postoperatively. Postoperative complications and ethmoid sinus inflammation scores were similar and compared favorably with Murr et al. 5. Clinical profile and post-marketing findings The PROPEL mini for the frontal sinus was approved in March 2016, based on the data from the PROGRESS study, a prospective randomized blinded study designed to evaluate its safety and efficacy. This study was preceded by three clinical trials and one meta-analysis evaluating the use of the PROPEL implant in the ethmoid sinus. These studies form the framework for the current use of steroid-eluting implants following FESS for the treatment of CRS PILOT study The first study validating the PROPEL stent implant in the ethmoid sinus was completed by Murr et al. This was a prospective randomized multicenter study investigating the effects of the PROPEL implant post-ethmoid sinus surgery [18]. A total of 43 patients undergoing FESS were assigned to 1 of 2 groups for 2 separate experiments. Group 1 (n = 38) 5.3. ADVANCE II trial The most recent study of the PROPEL implant in the ethmoid sinus was the ADVANCE II trial by Marple et al. This was a prospective multicenter trial that compared intra-patient results of a steroid-eluting steroid implant. A total of 105 CRS patients undergoing ethmoid sinus surgery using an intra-patient control study design were randomized with a steroid-eluting implant randomly assigned to one side and a nonsteroid-eluting stent assigned to the contralateral side. Recurrent polyposis, adhesions, and postoperative interventions were assessed by blinded reviewers using a standardized checklist and analyzed. Patients were assessed at 14, 30, 60, and 90 days intervals. The steroid-eluting implant provided a 29% relative reduction in postoperative interventions and 52% reduction in lysis of adhesions. A 44.9% relative reduction in polyposis was demonstrated in the treatment arm. The study also assessed the safety of the device by measuring intraocular pressures on the treatment and control sides. No

6 EXPERT REVIEW OF MEDICAL DEVICES 97 significant difference was found at sequential postoperative visits Meta-analysis of PROPEL implant Although the above-mentioned clinical trials showed positive results for the use of drug-eluting therapy in patient with chronic sinusitis, their power was limited. Since two of the studies had similar designs (Murr et al. and ADVANCE II by Marple et al.), the results were able to be pooled and published in a meta-analysis by Han [23]. The 30-day postoperative videos from these trials were evaluated by a 3-member panel to assess the need for oral steroids, surgical lysis of adhesion, and frank polyposis. If two-third of panel members agreed on a decision, the decision was final. According to the clinical investigation panel, the drug-eluting implants reduced the need for postoperative interventions by 35% (p = ). There was a relative reduction of 51% (p = ) in the need for surgical intervention for adhesions on the treated versus control sides. There was a 40% relative reduction (p = ) in the need for oral steroid intervention on the implanted sides. A 46% relative reduction in frank polyposis (p < ) was also noted on the implanted sides. Finally, there was a 75% relative reduction in middle turbinate lateralization and a 70% relative reduction in significant adhesions as assessed by clinical investigators. Ultimately, this study supported the use of steroid-eluting implants to reduce the frequency of postoperative interventions in the ethmoidal sinuses Studies investigating steroid-eluting implant in frontal sinus recess In 2014, Janisiewicez and Lee investigated potential uses of the steroid-eluting stent in frontal sinus recess, describing successful use of PROPEL mini following in-office balloon dilation of the frontal recesses in two patients [26]. Both patients had previously undergone endoscopic frontal sinus surgery and failed subsequent medical therapy. In-office balloon dilation and placement of steroid implant resulted in decreased inflammation in the frontal recess in these patients who had previously failed medical therapy over 6 and 11 months span. This report and other unpublished data signaled potential future use of this implant in the frontal recess of patients with chronic sinusitis. (surgical or medical). All patients received a 10-day course of postoperative antibiotics and were allowed to begin intranasal steroids on postoperative day 14. Postoperative interventions, defined as surgical debridement of obstructive adhesions or scar or medical need for oral steroids for recurrent inflammation and/or polyposis in the frontal sinus opening, were statistically significantly decreased in treated sinus sides. As judged by an independent reviewer, 38.8% of treated sides were determined to need a postoperative intervention (medical or surgical), compared to 62.7% of control sides. There was a 38.1% relative reduction in need for intervention in the implanted frontal sinus as judged by the clinical investigators; there was 55.6% relative reduction in need for oral steroid intervention and 75% relative reduction in need for surgical intervention favoring the implanted frontal sinus openings. These results were similar to the results for the PROPEL implant following ethmoidal sinus surgery and are currently the highest level of evidence for efficacy of PROPEL mini following frontal sinus surgery. 6. Alternative steroid delivery mechanism The recent advent of steroid-eluting implants has precluded a plethora of alternatives, although of use several steroid compounds through local delivery mechanisms have been previously investigated [27]. Polyvinyl acetate foam, carboxymethylcellulose, and polyurethane foam in association with some steroid compound have all been delivered locally to the ethmoid, attempted after FESS (see table 3). None explored local delivery of steroid to the frontal sinus opening except for an off-label use of a balloon device filled with steroid solution. This device is no longer available on the market Nonabsorbable steroid delivery compounds Chang et al. investigated the use of polyvinyl acetate foam, a nonabsorbable nasal packing material, as a steroid impregnated packing device of the middle meatus following FESS. In this prospective study, an intra-patient control of nonsteroid impregnated foam was used to compare results. A trend toward reduced mucosal inflammation was observed over a 7-day postoperative course with the steroid impregnated sponge, but results were not statistically significant [28] PROGRESS study The PROGRESS study formed the basis for FDA approval of PROPEL mini implant for use in the frontal recess following frontal sinus surgery. Smith et al. assessed the safety and efficacy of the PROPEL mini following frontal sinus surgery in a prospective, randomized, blinded multicenter US study that involved 80 patients across 11 institutions [22]. The study used an intra-patient control: surgery + PROPEL mini versus surgery alone following successful bilateral frontal sinus surgery, in which one frontal sinus opening received the drug-eluting implant and the other did not. The primary end points included reduction in the need for postoperative interventions 6.2. Absorbable steroid delivery compound A middle meatal spacer of plant-based composition, carboxymethylcellulose, was trialed by Rudmik et al., in a doubleblinded placebo controlled trial. Postoperative follow-up extended over a 3-month period. Results were similar between placebo and treatment and did not demonstrate improved endoscopic outcomes over the observation course [29]. Cote and Wright evaluated the impact of steroid impregnated polyurethane foam (a bioabsorbable packing) following FESS in 19 patients over 6-month period. Outcomes measured were limited to preoperative sinus endoscopy (POSE) and Lund Mackay scores the need for postoperative

7 98 S. BURY AND A. SINGH interventions was not measured. At the conclusion of the study at 6 months, 16 patients remained. The treated population had an average POSE score of 5.2 and Lund Mackay score of The control population had an average POSE score of 6.5 and Lund Mackay score of This result was found to be statistically significant [30] Status of PROPEL mini The PROPEL mini is the only FDA-approved implant technology indicated to reduce the need for post- operative interventions (medical or surgical) in the frontal sinus after FESS. As such, it is in a unique class, and directly comparable technologies do not yet exist. 7. Safety overview The systemic effects of steroid-eluting implants have generally been regarded as minimal. Data from animal and human studies both show low-to-none systemic absorption, and the tabulated side effects (i.e. intraocular pressure) have failed to show a statistical difference from controls. Steroid-eluting stents deliver a stable dose of drug over time. The PROPEL mini locally delivers 370 µg of MF over 45 days. For purposes of comparison, MF nasal steroid spray has a recommended dose of 200 µg/day for allergic rhinitis and 400 µg/day for nasal polyps. This shows that the total dose delivered by PROPEL mini over 45 days is less than the recommended daily dose of MF for nasal polyp patients. Repeated studies have demonstrated that nebulizer doses from 100 μg once daily to 400 μg twice daily for periods ranging from 21 days to 52 weeks do not result in suppression of the hypothalamic pituitary axis as measured by 24-h urinary cortisol, cosyntropin production, or serum cortisol [31 38]. Li et al. first investigated the systemic absorption of steroideluting implants in a rabbit model and demonstrated very low systemic absorption. Twenty-five rabbits weighing between 4 and 5 kg received two steroid-eluting stents containing 100 µg of MF each (a proportionally much higher concentration than humans). Rabbit plasma was evaluated for MF concentrations over time using mass spectrometry and peaked at 62 ng/ml in the first rest week, with plasma concentrations unquantifiable after the second week [39]. Murr et al. investigated the effects of PROPEL mini on cortisol levels in the PILOT study. Five patients received serial blood draws prior to surgery and at days 7, 14, 21, and 30. Blood samples were analyzed for plasma MF and cortisol levels after each draw with a lower limit of quantification at 30 pg/ml. Plasma cortisol levels were drawn before 10 am and all plasma cortisol levels were within normal daytime values with the exception of one patient who had two samples that demonstrated decreased plasma cortisol preoperatively and at day 21. All plasma MF levels were below the lower limit of quantification [18]. The data from the PILOT study are consistent with prior research on MF and demonstrate low systemic absorption and low potential for systemic effects. Future research may seek to elucidate the maximal limit of steroid dose in steroid-eluting implants. 8. Conclusion The studies to date have demonstrated that steroid-eluting implants are beneficial in reducing postoperative medical or surgical interventions for patients with chronic sinusitis undergoing ethmoid sinus surgery (see table 2). There is a single Table 2. Clinical trials of steroid releasing implants. Study Authors Device Location Population Intra-patient control Outcomes measured PILOT Murr et al. PROPEL Ethmoid n = 43 Yes (1) Endoscopic inflammation (2) Polyp formation (3) Significant adhesion (4) Middle turbinate lateralization ADVANCE Forwith et al. PROPEL Ethmoid n = 50 No (1) Endoscopic inflammation (2) Intraocular pressure (systemic toxicity) (3) Percent of implant remaining over time (4) SNOT-22/RSDI scores (5) Polypoid tissue (6) Significant adhesion (7) Middle turbinate lateralization ADVANCE II Marple et al. PROPEL Ethmoid n = 105 Yes (1) Need for postoperative intervention (2) Frank polyposis (3) Middle turbinate lateralization (4) Significant adhesion Followup 60 days 60 days 90 days PROGRESS Smith et al. PROPEL mini Frontal n = 80 Yes (1) Endoscopic inflammation (2) Frequency of Polyp formation (3) Significant adhesion (4) Middle turbinate lateralization (5) Percent of implant remaining over time (6) Plasma levels Of MF/adrenocortical suppression (systemic toxicity) 60 Days

8 EXPERT REVIEW OF MEDICAL DEVICES 99 Table 3. Selected steroid delivery devices post-fess. Device Active ingredient Absorbable Statistically significant results Studies measured outcomes FDA approved for ethmoidal sinus PVA foam Budesonide No No No No No CBC Dexamethasone Yes No No No No PUF 2 ml of 40 mg/ml Yes Yes No No No triamcinolone FDA approved for frontal sinus PROPEL stent 370 µg MF Yes Yes Yes Yes No PROPEL mini 370 µg MF Yes Yes Yes Yes Yes randomized, blinded multicenter study assessing safety and efficacy of the PROPEL mini specifically in the frontal sinus. The results in the frontal sinus are similar to data generated for ethmoid surgery with a decreased need for medical and surgical postoperative interventions. Furthermore, economic models have demonstrated steroideluting implants to be cost-effective when evaluated over the 60-day postoperative period. There are no data for cost-effectiveness in steroid-eluting implants in the frontal sinus, but given the congruence in efficacy between clinical models, it is reasonable to suspect congruence in economic models as well. The safety of steroid-eluting implants at the current dose is well accepted. MF is understood to be a safe drug for the treatment of chronic sinusitis, and implant dosing regimens do not exceed dosing for chronic sinusitis. Systemic side effects have not been demonstrated in the initial randomized studies; cortisol level of patients with steroid-eluting implants is undetectable. 9. Expert commentary 9.1. Current treatment Oral and topical steroids have been the mainstay of treatment for chronic sinusitis. Oral steroids, in particular, have been extensively utilized in patients with recalcitrant chronic sinusitis or chronic sinusitis with nasal polyposis. However, oral steroids are not without significant detrimental short and long-term systemic side effects. The availability of steroideluting implants for local drug therapy has been one of the more significant recent developments in the treatment of patients with chronic sinusitis Steroid implants Although some questions regarding their efficacy, value, and cost-effectiveness have been posed, the current body of literature suggests that these implants improve outcomes with acceptable cost that may translate to savings in the long-term management of this disease entity. Local drug delivery is widely considered across multiple disciplines to be beneficial to patients given their directed therapy while minimizing systemic side effects. This is especially true in the paranasal sinuses where therapy is delivered using the body s natural conduits. To-date, two randomized trials, and one meta-analysis, have validated the benefits of these implants in the ethmoid sinus. The recent PROGRESS study represents the one and only randomized blinded trial that has demonstrated the safety and efficacy of the implant in the frontal sinus after endoscopic sinus surgery. Although other methods of locally delivering steroids to the paranasal sinuses have been explored, these have not been rigorously studied. The PROPEL mini can be endoscopically placed in the frontal sinus opening after FESS or balloon sinuplasty, thereby locally delivering steroid to the tissues to reduce inflammation, scarring, and ostial stenosis. No other implant exists to deliver steroid to the frontal sinus opening, let alone extensively evaluated for drug delivery, resorption among several other parameters. PROPEL mini improves patient outcomes in the frontal sinus when measured by the need for medical and surgical postoperative interventions Future research Although this objective data for use of PROPEL mini are compelling, additional randomized control studies with larger, diverse subgroups of patient populations could further delineate its use. Increased duration of follow-up in future studies (current studies are limited to 30 days follow-up for the PROPEL mini) will allow better assessment of clinical and economic efficacy. Additional clinical applications in the frontal sinus among the different subgroups of chronic sinusitis patients will better define the optimal utilization of the implant. 10. Five-year view Renowned physicist Niels Bohr stated Prediction is very difficult, especially if it s about the future. This accuracy of this statement is undeniable, and the best medical professionals can do is base their predictions on proven facts and observation of trends. Nasal steroids have long been recognized to be beneficial to address inflammation in patients with chronic sinusitis. Delivery of steroid to the frontal sinus given its location and narrow access has always been problematic. In addition, postoperative healing after endoscopic frontal sinus surgery is fraught with potential for scarring, stenosis, and recurrent inflammation. PROPEL mini addresses a critical need for sustained, localized steroid drug delivery to the frontal sinus opening after endoscopic surgery for chronic sinusitis. Recent studies have shown PROPEL mini, the only FDA approved steroid-eluting implant to be effective at reducing poor frontal sinus surgical outcomes. The need for localized drug delivery for the paranasal sinuses combined with encouraging data for PROPEL and PROPEL mini suggests great potential for continued variations of drug delivery for the paranasal sinuses. Some of the potential advancements include increased dosage of steroids while

9 100 S. BURY AND A. SINGH minimizing local toxicity, longer rate of drug delivery, changes in design, and confirmation. Key issues Ensuring patency of frontal sinus and preventing recurrent frontoethmoidal inflammation following endoscopic sinus surgery is a challenge for otolaryngologists Steroid eluting implants are the only FDA approved technology following frontal sinus surgery shown to decrease the need for post operative interventions and improve outcomes in patients with chronic sinusitis Early data supports the cost effectiveness of steroid eluting implants for patients with chronic sinusitis over a 6 month post-operative period Mometasone furoate, the active ingredient, has been proven safe in treatment of chronic sinusitis. Steroid eluting implants at the current dose have not been shown to display systemic side effects (i.e. intraocular pressure) or increase serum cortisol levels. There is significant potential for growth in the use of steroid eluting implants in the paranasal sinuses for patients suffering from chronic sinusitis. Information Resources The four clinical trials (PILOT, ADVANCE, ADVANCE II, PROGRESS) provide the strongest evidence for use of steroid eluting implants following sinus surgery, with the PROGRESS study exclusively addressing the frontal sinus. Economic studies are noted in annotated bibliography below. Currently there is one manufactur er who has FDA approval for steroid eluting implants of the frontal sinus (Intersect ENT), and their website ( has material demonstrating use and mechanics of the device. Coding information may be found at an industry sponsored site ( pens.com). Note 1. This paragraph utilizes several economic terms. Third party payer is when a third party, such as an insurance company, pays healthcare provider for services rendered. Willingness to pay is a term from economics used in cost benefit analysis for expected health outcomes. In this study, the context of terms refers to how much an insurance company is willing to spend in an insured population. Funding This paper was not funded. Declaration of interest A. Singh is a consultant for and has received research funding from Intersect ENT. A. Singh has also participated in clinical studies for Intersect ENT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. References Papers of special note have been highlighted as either of interest ( ) orof considerable interest ( ) to readers. 1. Halawi AM, Smith SS, Chandra RK. Chronic rhinosinusitis: epidemiology andcost. Allergy Asthma Proc Jul-Aug;34(4): PubMed PMID: DOI: /aap Review 2. Bhattacharyya N. 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