Bij bepaalde patiënten met chronische rhinosinusitis (CRS) doen zich klachten voor die ondanks optimale medicamenteuze en chirurgische interventies onvoldoende kunnen worden beteugeld. Ook na gerichte chirurgie kunnen zich drainage problemen voordoen en de drainageroutes worden verstoord. Hiernaast kan de mucosale ontsteking een belangrijke rol spelen.  De invloed van de chronische ontsteking op de mucosa en de benige begrenzingen (airway remodelling) weerspiegelt de ernst van de CRS. De rol van stents met lokale corticosteroïden met langdurige vertraagde afgifte op deze mucosale problematiek is mogelijk zinvol als supplement. Navigatie is een ondersteunende techniek bij de ovewegend complexe en revisie ingrepen van de sinus. Dit zal door de operateur moeten worden beoordeeld.

Description of studies

Bioabsorable steroid/antibiotic-impregnated nasal packing

Wierzchowska (2021) performed a randomized, double-blind, placebo-controlled study to evaluate the effects and morbidities of using NasoPore combined with antibiotic (ciprofloxacin), steroid (betamethasone), or the combination of both on the postoperative healing process and the quality of life in adult patients, after endoscopic sinus surgery. Participants were recruited randomly from the adult patients diagnosed with chronic rhinosinusitis, both with and without polyps, having received refractory to maximal medical treatment and qualified for bilateral FESS. Exclusion criteria were patients with signs of acute infection. One hundred twenty patients (71 men and 49 women) with a mean age of 44.68 year were enrolled in the study. The enrolled patients were randomized by a computer-generated program and having been assigned their numbers, allocated to 3 groups, 40 participants each, according to the following code: antibiotic (A)—ciprofloxacin (Ciprinol 10 mg/mL), steroid (S)—betamethasone (Diprophos 7 mg/mL) and the combination of both (AS).

Steroid implants (Propel and sinuva)

Han (2019) performed a literature review to evaluate steroid-eluting implants in CRS patients after ESS. Studies about two modes of steroid-eluting sinus implants were included:

• Propel family products (Propel, Propel Mini, Propel Contour; Intersect ENT, Menlo Park, CA) (Murr, 2011; Marple, 2012; Smith, 2016; Luong, 2018 );
• Sinuva (Intersect ENT, Menlo Park, CA) (Han, 2014; Kern, 2018).

The individual studies are included in the literature analysis.

Murr (2011) performed a prospective, multicenter, randomized, double-blind clinical trial to examine the safety and efficacy of a corticosteroid eluting stent in patients undergoing FESS for CRS. The study population included adult patients with or without nasal polyps scheduled to undergo primary or revision FESS, and in whom placement of the sinus stents was deemed to be both feasible and medically appropriate. A total of 43 patients were enrolled between March 2008 and February 2009, of which 58% was men and a mean age of 47.5 years. Thirty-eight patients were enrolled into the intrapatient control design cohort, comparing drug-eluting to non-drug-eluting stents. Five patients were enrolled in the other group and received bilateral drug-eluting stents to assess systemic safety.

Smith (2016) performed a prospective, multicenter, randomized, blinded trial to assess the safety and efficacy of the steroid- releasing sinus implant in reducing the need for postoperative interventions when placed in the FSO of CRS patients undergoing ESS. The study population included adult (³ 18 years of age) patients diagnosed with CRS based on American Academy of Otolaryngology–Head and Neck Surgery guidelines1 who were scheduled to undergo primary or revision bilateral ESS and had evidence of bilateral frontal sinus disease based on computed tomography (Lund-Mackay score of ³ 1 on each side). Patients who had known history of immune deficiency or insulin-dependent diabetes, clinical evidence of acute bacterial or invasive fungal sinusitis, or any oral-steroid dependent condition were excluded from the study. From September 2014 through June 2015, a total of 89 patients were consented for screening; of those, 80 met final eligibility criteria and were randomized. The mean (± standard deviation [SD]) age of patients randomized in the study was 49.9 years (13.9), and 57.5% were male

Luong (2018) performed a prospective, multicenter, randomized clinical trial to assess the safety and efficacy of the hourglass-shaped, bioabsorbable, steroid-releasing sinus implant in improving postoperative outcomes when placed in the frontal sinus ostia (FSO) following ESS in patients with chronic rhinosinusitis (CRS). The study population included adult patients diagnosed with CRS based on AAO-HNS guidelines,3 who were scheduled to undergo primary or revision bilateral ESS and had evidence of bilateral frontal sinus disease based on computed tomographic (CT) scan (Lund-Mackay [L-M] score of ≥1 on each side). Patients who had known medical his- tory of immune deficiency or insulin-dependent diabetes, clinical evidence of acute bacterial or invasive fungal sinusitis, or any oral steroid-dependent condition were excluded. Between July 2015 and March 2016, 80 patients consented, met all eligibility criteria, and were randomly assigned to receive a steroid-releasing implant in one of the frontal sinus ostia, after successful bilateral frontal sinusotomies. The mean (SD) age of patients was 49.5 (13.4) years, 53 (66%) were men, and 41 (51%) patients had at least 1 prior ESS.

Han (2014) performed a randomized controlled blinded study to assess the safety and efficacy of the steroid-eluting sinus implant inserted in the office setting in post–sinus surgery patients who present with recurrent ethmoid obstruction due to NP. Adult patients were included if they were at least 18 years old, had been diagnosed with CRS, and had undergone prior bilateral total ethmoidectomy more than 3 months earlier. A total of 183 patients were consented for screening between January and November 2013, of whom 100 met eligibility criteria and were randomized to either the treatment (n = 53) or the control (n = 47) group. The mean age (range) in the treatment and control group were 47.8 year (19-74) and 51.6 year (30-80), respectively. The number of males in the treatment and control group were 29 (54.7%) and 31 (66%), respectively. 

Kern (2018) performed a randomized, sham-controlled, double-blind trial to evaluate the safety and efficacy of a bioabsorbable corticosteroid-eluting sinus implant (SINUVATM Sinus Implant, Intersect ENT, Inc., Menlo Park, CA), containing 1350 μg of mometasone furoate (MF). Patients were enrolled from December 2014 to May 2016 at 34 clinical sites across the United States. Eligibility was confirmed based on an electronic diary of nasal obstruction/congestion symptoms over the first 7 days of the 14-day run-in screening period using INCS and grading of videoendoscopies by an independent reviewer. Eligible patients were randomized (2:1) to the treatment or control group using an electronic data capture system and underwent either bilateral implant placement or sham procedure. Of the 531 patients enrolled and screened, 300 were randomized and underwent a baseline procedure. The ITT population comprised 201 treatment and 99 control patients. The mean age (± SD) in the treatment and control group were 50.5 ± 12.9 and 47.9 ± 12.4 years, respectively. The number of males in the treatment and control group were 127 (63.2%) and 56 (56.6%), respectively. 

Results

Bioabsorable steroid-impregnated nasal packing

PROMs (SNOT-22, TNSS, VAS)

The included study did not report outcome measure “ PROMs” with the use of the SNOT-22 or TNSS.

Wierzchowska (2021) reported patients’ complaints with the use of a Visual Analogue Scale in postoperative days, including facial pressure and nasal blockage.

Nasal polyp score

The included study did not report the outcome measure “nasal polyp score” for bioabsorable steroid-impregnated nasal packing.

Sense of smell/olfactory dysfunction

Wierzchowska (2021) reported sense of smell with the use of a Visual Analogue Scale in postoperative days.

Adverse events

The included study did not report the outcome measure “adverse events” for bioabsorable steroid-impregnated nasal packing.

Level of evidence of the literature

The level of evidence regarding the outcome measures “patient complaints (PROM)” and “sense of smell” comes from a randomized controlled trial and therefore starts at high. The level of evidence was downgraded by three levels because of study limitations due to selective outcome reporting and doubt about the quality of the results (risk of bias, -2) and low numbers of included patients (imprecision, -1), resulting in a level of evidence of very low.

Level of evidence of the literature

The level of evidence could not be assessed for the outcome measures “nasal polyp score” and “adverse events”, because the included study did not report these outcome measures for bioabsorable steroid-impregnated nasal packing.

Conclusions

Steroid implants (Propel and sinuva)

PROMs

Han (2019) reported the outcome measure patient-reported outcomes in one randomized controlled trial (Han, 2014).

Han (2014) reported that the treatment group improved symptomatically over 90 days. Compared to control, the treatment group experienced a 2-fold reduction in nasal obstruction and congestion score at day 90. The change from baseline in the treatment group was −1.33 ± 1.5 on the 5-point scale compared to −0.67 ± 1.5 in the control. A mean difference of -0.66 (95% CI: -1.25 to -0.07) favoring the treatment group was calculated, which is not clinically relevant.

Nasal polyp score

Han (2019) reported the outcome measure nasal polyp score in one randomized controlled trial (Kern, 2018).

Kern (2018) reported a bilateral polyp grade change from baseline to day 90 (scale 0-8) of -0.56 ± 1.06 and -0.15 ± 0.91 in the treatment (n=195) and control group (n=97), respectively. A mean difference of -0.41 (95% CI: -0.64 to -0.18) was calculated favoring the treatment group, which is not clinically relevant.

Sense of smell/olfactory dysfunction

Han (2019) reported the outcome measure sense of smell in one randomized controlled trial (Kern, 2018).

Kern (2018) reported a decreases sense of smell score change from baseline to day 90 (scale 0-5) of -1.20 ± 1.66 and -0.76 ± 1.60 in the treatment (n=198) and control group (n=97), respectively.  A mean difference of -0.44 (95% CI: -0.83 to -0.05) favoring the treatment group was calculated, which is not clinically relevant.

(serious) Adverse events (short and long term)

Han (2019) reported in three randomized controlled trial the outcome measure adverse events (Smith, 2016; Luong, 2017; Han, 2014).

Smith (2016) reported no implant-related adverse events in the study. Five adverse events (headache, left upper eyelid swelling, epistaxis, recurrent chronic sinusitis, and increased sinus pressure) were judged by the clinical investigators to have an indeterminate relationship to the implant. A total of four serious adverse events (diverticulitis, pulmonary fungal infection, two events of deep vein thrombosis) were reported among three patients in the study.

Luong (2017) reported no implant-related adverse events in the study. There were three adverse events that were judged by clinical investigators to have an indeterminate relationship to the implant and drug from the implant (headache, epistaxis, and acute sinusitis).

Both studies did not report how many patients experienced adverse events, therefore GRADE could not be assessed.

Han (2014) reported no serious adverse events during the study. The overall incidence of adverse events, the majority of which were considered related to sinusitis, was similar between the groups. There were 34 (64%) patients in the treatment group and 35 (75%) in the control group who experienced an adverse event of any type. A risk ratio of 0.86 (95% CI: 0.66 to 1.12) favoring the treatment group was calculated, which is not clinically relevant.

Level of evidence of the literature

The level of evidence regarding the outcome measures “patient-reported outcome” comes from a randomized controlled trial and therefore starts at high. The level of evidence was downgraded by two levels because of study limitations due to lack of blinding of clinical investigators (risk of bias, -1) and crossing the lower limit of clinical relevance (imprecision, -1), resulting in a level of evidence of low.

The level of evidence regarding the outcome measures “nasal polyp score” comes from a randomized controlled trial and therefore starts at high. The level of evidence was downgraded by one level because of study limitations due to lack of allocation concealment (risk of bias, -1), resulting in a level of evidence of moderate.

The level of evidence regarding the outcome measures “sense of smell” comes from a randomized controlled trial and therefore starts at high. The level of evidence was downgraded by two levels because of study limitations due to lack of blinding of clinical investigators (risk of bias, -1) and crossing the lower limit of clinical relevance (imprecision, -1), resulting in a level of evidence of low.

The level of evidence regarding the outcome measures “adverse events” comes from a randomized controlled trial and therefore starts at high. The level of evidence was downgraded by two levels because of study limitations due to lack of blinding of clinical investigators (risk of bias, -1) and crossing the lower limit of clinical relevance (imprecision, -1), resulting in a level of evidence of low.

A systematic review of the literature was performed to answer the following question: What are the benefits and harms of a slow-releasing corticosteroid implant after surgery in patients with chronic rinosinusitiswith/without nasal polyps compared to standard of care?

P: Patients with chronic rinosinusitiswith/without nasal polyps undergoing surgery.

I: Slow releasing corticosteroïd implant.

C: Placebo or usual care.

O: PROMs (SNOT-22, TNSS, VAS), nasal polyp score, sense of smell/olfactory dysfunction, (serious) adverse events (short and long term).

Relevant outcome measures

The guideline development group considered patient reported outcome measures (PROMs) as critical outcomes for decision making; and the outcomes nasal polyp score, sense of smell/olfactory dysfunction, and (serious) adverse events as important outcomes for decision making.

A priori, the working group considered disease-related quality of life, as assessed by the Sino-Nasal Outcome Test (SNOT-22) score, the preferred outcome. This is a quality of life score specifically for CRS patients, in which patients score the burden of disease for 22 symptoms and social/emotional consequences from 0 (“no problem”) to 5 (“problem as bad as it can be”), resulting in a total score from 0 to 110. In case SNOT-22 was not reported, symptom severity as described by total nasal symptom score was preferred over the use of a visual analogue score (VAS). In the VAS the patient expresses symptom severity on a 10 cm broad horizontal line with word anchors at each end that indicate the extreme feelings. The important outcomes nasal polyp score and sense of smell/olfactory dysfunction could be assessed by any validated score. Adverse events were not defined a priori, but a distinction is made between adverse and serious adverse events, both in the short and long term.

For the SNOT-22 score the working group defined 12.0 as a minimal clinically (patient) important difference (MCID) in medically managed patients with CRS, as described in literature (Phillips, 2018). For total symptom score, polyp score and VAS scores, the working group defined 15% of the maximum score as MCID, and 0.5 for standardized mean differences. For adverse events (risk ratio, RR), the working group defined 25% as a MCID.

Search and select (Methods)

The meta-analysis of the EPOS position paper (Fokkens, 2020) was followed, and updated with papers published more recently (2019 and later). The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until January 24, 2022. The detailed search strategy is depicted under the tab ‘Methods’. The systematic literature search resulted in 87 hits. Studies were selected based on the following criteria: systematic reviews and randomized controlled trials on the effects of slow-releasing implants in patients with CRS with/without nasal polyps. 19 studies were initially selected based on title and abstract screening. After reading the full text, 17 studies were excluded (see the table with reasons for exclusion under the tab ‘Methods’), and two studies were included.

Results

Two studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.