Question | |
Should any specific individual intranasal glucocorticosteroid vs. other individual intranasal glucocorticosteroids be used for allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | any specific individual intranasal glucocorticosteroid |
Comparison: | other individual intranasal glucocorticosteroids |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | |
Background: | There are several intranasal corticosteroids available, rendering it important not only to provide recommendations at a class level but also on what may be the most indicated individual intranasal corticosteroids. |
Conflict of interests: | AWMF conflict of interest declaration and management policies were applied, the assessment performed by the AWMF with guidance and help from Juan Jose Yepes Nuñez. |
Assessment
ProblemIs the problem a priority? | ||
Judgement | Research evidence | Additional considerations |
Allergic rhinitis (AR) is a common condition affecting 18.1% of the population, and its symptoms can significantly reduce the quality of life and pose a high economic burden (mainly because of indirect costs related to lost school days and workdays). [Savoure] Studies of patients consulting general practitioners for AR reported that 18–48 % had symptoms that were not controlled by pharmacotherapy. [Bousquet, Bhattacharyya, Vandenplas] Despite the bothersome nature of symptoms, AR is often trivialized by the patient - only 45% seek medical advice or treatment for their condition, which results in under-treatment and poor control of symptoms. [Linneberg] Problems related to disease Economic burden A systematic review performed to estimate the financial burden of AR in European countries [Linneberg] suggests that the GP services bore the majority of the direct costs for AR. However, the majority of the overall cost burden correspond to indirect costs caused by high absenteeism and presenteeism. In the United States, annual costs for medications for rhinitis patients can be estimated at approximately $1.3 billion. In total, direct costs are estimated to be >$4.6 billion for rhinitis management, including treatment, allergy testing, clinical visits and hospital procedures. [Roland] Similar findings were found for Asia. An analysis of the indirect costs associated with insufficiently treated AR and urticaria patients revealed an annual burden of USD 105.4 billion. This translates to a cost ranging from USD 1,137 to USD 2,195 per patient due to absenteeism and presenteeism [ Kulthanan] Clinical burden The median prevalence of allergic rhinitis was found to be 18.1%, based on a dataset that included 310 reported prevalences. The prevalence of AR ranged from as low as 1.0% to as high as 54.5%.
These statistics indicate that AR is a relatively common condition affecting a significant portion of the population, with variations in prevalence observed across different regions or studies. [Savouré] Problems related to intervention Based on a conducted rapid review, several barriers and concerns related to the feasibility of intranasal corticosteroids for patients with AR have been identified. These barriers are related to safety, knowledge, cost, and effectiveness. The extent to which these barriers pose problems in feasibility may vary depending on the specific patient population and regional differences. References:
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Desirable EffectsHow substantial are the desirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Nasal symptoms In a systematic review with network meta-analysis performed by Sousa-Pinto et al., the improvement of nasal symptoms was assessed in patients under intranasal corticosteroids (INCS). For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total nasal symptom score (TNSS) results of 68 randomised controlled trials (RCTs). All INCS were associated with a significantly higher improvement in the TNSS when compared to placebo (for fluticasone furoate, fluticasone propionate and budesonide there is more than 50% probability that a moderate improvement in the TNSS is observed). In addition, fluticasone furoate and fluticasone propionate displayed significantly better results than ciclesonide and mometasone furoate (however, there is more than 50% probability that these differences are not clinically meaningful). Fluticasone furoate and fluticasone propionate were the INCSs displaying the highest probability of being the most effective in improving the TNSS. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 26 RCTs. All INCS were associated with a significantly higher improvement in the TNSS when compared to placebo; except for budesonide (moderate difference), all INCS were associated with a small improvement in the TNSS compared to placebo. There were no significant differences in the comparisons between different INCSs. Budesonide (followed by beclomethasone, fluticasone furoate and mometasone furoate) was the INCS displaying the highest probability of being the most effective in improving the TNSS, but it was assessed by a single RCT. Subgroup considerations: Asthma vs. No asthma A subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. The following results (with the corresponding p-scores) were found:  Subgroup considerations: Children and adolescents A subgroup analysis of studies in children and adolescents was not performed due to insufficient number of primary studies assessing each individual medication. Ocular symptoms In a systematic review with network meta-analysis performed by Sousa-Pinto et al., the improvement of ocular symptoms was assessed in patients under INCS. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total ocular symptom score (TOSS) results of 21 RCTs. Except for ciclesonide, INCS were associated with a significantly higher improvement in the TOSS when compared to placebo. In addition, except ciclesonide and mometasone (trivial effect), all the remaining INCS were associated with a small improvement of TOSS compared to placebo. There were no significant differences in the comparisons between different INCSs. Beclomethasone and fluticasone furoate were the INCSs displaying the highest probability of being the most effective in improving the TOSS. For patients with perennial allergic rhinitis, only fluticasone furoate and mometasone furoate were assessed. Fluticasone resulted in a significant TOSS improvement compared to placebo, but the same was not observed with mometasone. Subgroup considerations: Asthma vs. No asthmaA subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. The following results (with the corresponding p-scores) were found [only data for seasonal allergic rhinitis were available]:  Subgroup considerations: Children and adolescentsA subgroup analysis of studies in children and adolescents was not performed due to insufficient number of primary studies assessing each individual medication. Overall symptoms In a systematic review with meta-analysis performed by Sousa-Pinto et al., the improvement of overall symptoms was assessed in patients under INCS. The patient-reported outcome measure used to assess this outcome was the total symptom score (TSS), which includes nasal, ocular and other rhinitis symptoms. The TSS computing method differed among studies, and while in most it consisted of the sum of nasal and ocular symptoms, in other RCTs ear and/or palatal itching, post-nasal drip or cough were part of the TSS. For seasonal allergic rhinitis (SAR), 8 RCTs reported TSS values: 2 for beclomethasone, 5 for mometasone and 1 for triamcinolone. The included RCTs only presented comparisons versus placebo. In two studies assessing beclomethasone (different doses), significant differences in the change from baseline TSS were observed in the beclomethasone group vs placebo. Mometasone was associated with a significant improvement on the TSS score vs placebo in 4 out of the 5 RCTs assessing this outcome for SAR. In one of these studies, however, only the difference in morning TSS was reported as significant (<0.029). It should be noted that the only study in which the improvement on the TSS was not significant compared to placebo did not provide any details on the TSS computation method. The only study on triamcinolone nasal spray (220 μg) for the treatment of SAR did not show a significant improvement in the change from baseline TSS compared to placebo (MD=-0.2; p=0.84). For perennial allergic rhinitis (PAR) , only 2 studies assessed the improvement on the TSS at the end of a 4-week period treatment with two different INCS: mometasone and triamcinolone. The included RCTs only presented comparisons versus placebo. The study comparing the TSS (0-15 scale) improvement in patients treated with mometasone vs placebo reported a non statistically significant difference between the two groups favouring mometasone (-5.0 vs -4.0: no p value or other details provided). The second study assessing patients with PAR only reported that a p-value=0.02 was found for the comparison between triamcinolone and placebo. Quality-of-life In a systematic review with network meta-analysis performed by Sousa-Pinto et al., the improvement of quality-of-life was assessed in patients under INCS. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the rhinocojunctivitis quality of life questionnaire (RQLQ) results of 23 RCTs. Fluticasone furoate displayed significantly better results than beclomethasone, ciclesonide, mometasone and triamcinolone. With the exception of fluticasone furoate (moderate improvement), all INCSs were associated with a small RQLQ improvement compared to placebo. Fluticasone furoate was also associated with significant improvements in the RQLQ compared to mometasone (more than 50% probability of resulting in a small meaningful improvement). Fluticasone furoate and fluticasone propionate were the INCSs displaying the highest probability of being the most effective in improving the RQLQ. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 13 RCTs. Except for fluticasone propionate and triamcinolone, all INCS were associated with a significantly higher improvement in the RQLQ when compared to placebo (differences were most probably small for most INCSs [except mometasone - moderate improvement]). There were no significant differences in the comparisons between different INCSs. Fluticasone furoate and beclomethasone were the INCS displaying the highest probability of being the most effective in improving the RQLQ. Subgroup considerations: Asthma vs. No asthma A subsequent subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al. was performed, grouping trials according to whether they had excluded patients with asthma. The following results (with the corresponding p-scores) were found [only data for seasonal allergic rhinitis were available]:  Subgroup considerations: Children and adolescents A subgroup analysis of studies in children and adolescents was not performed due to insufficient number of primary studies assessing each individual medication. The summary of findings tables supporting the research evidence and the underlying references can be found here. | ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Adverse events In a systematic review with network meta-analysis performed by Sousa-Pinto et al., the frequency of patients developing at least one adverse event was assessed in patients under intranasal corticosteroids (INCS). A total of 80 randomised controlled trials (RCTs) reported data on the number of patients with seasonal allergic rhinitis reporting at least one adverse event. The only noteworthy difference between different INCS was that budesonide was the associated with a higher risk than fluticasone propionate or mometasone (small increases in the risk of adverse events). For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 36 RCTs. There were no significant differences in the comparisons between different INCSs. In an additional analysis of pharmacovigilance data comparing different individual INCS, no substantial differences in adverse events were found between individual drugs within the INCS class. Subgroup considerations: Asthma vs. No asthma No relevant differences on the frequency of adverse events between INCS were found when assessing the subgroups of studies excluding asthma patients or those not excluding those patients. Subgroup considerations: Children and adolescents A subgroup analysis of studies in children and adolescents was not performed due to insufficient number of primary studies assessing each individual medication. Serious adverse events In a systematic review with network meta-analysis performed by Sousa-Pinto et al., the frequency of patients developing at least one serious adverse event was assessed in patients under INCS. However, the frequency of events was too scarce to perform network meta-analysis comparing individual medications. The (non-pooled) frequency of serious adverse events per individual INCS is displayed in the following table. The provided intervals are fully within the “trivial” category.  In an additional analysis of pharmacovigilance data comparing different individual INCS, no substantial differences in important adverse events were found between individual drugs within the INCS class. Subgroup considerations: Asthma vs. No asthma Evidence was too scarce to perform a subgroup comparison in patients with asthma versus those with no asthma. Subgroup considerations: Children and adolescents A subgroup analysis of studies in children and adolescents was not performed due to insufficient number of primary studies assessing each individual medication. | ||
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
For all analyses, evidence was mostly of very low or of low certainty. Low certainty analyses were more common than very low certainty analyses. | ||
ValuesIs there important uncertainty about or variability in how much people value the main outcomes? | ||
Judgement | Research evidence | Additional considerations |
Utility values Symptoms Regarding specific symptoms, in two studies, utilities (measured by VAS) were lower for severe nasal congestion and severe rhinorrhea compared to severe sneezing, severe throat itching, and severe itchy eyes (certainty of evidence: low). When utilities were elicited with the standard gamble technique, severe itchy eyes were rated by US patients as the least preferred AR symptom (certainty of evidence: low).  Inc - Certainty of evidence was lowered due to inconsistency; R- Certainty of evidence was lowered due to risk of bias; Ind- Certainty of evidence was lowered due to indirectness; Imp- Certainty of evidence was lowered due to imprecision, ⨁⨁⨁⨁ high certainty of evidence, ⨁⨁⨁◯ moderate certainty of evidence, ⨁⨁◯◯ low certainty of evidence 4 We rated down the certainty of evidence for indirectness because an indirect measurement tool was used to elicit the utility of outcomes with scale of 0 to 1, where 0 indicated the worst symptom(s) and 1 represented no symptom(s). 5 Small sample size of the included study. Studies of rating or ranking of outcomes Adults
 Children/caregivers sample Seven studies assessing children or their caregivers were included in the relative importance analysis. Most of these studies only assessed symptom-related attributes. Similarly to the adult population, a nasal symptom was frequently ranked as the most or second most important attribute (certainty of evidence: low). In particular, nasal congestion was identified as the most important attribute in five studies (certainty of evidence: low).  | ||
Balance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
Taking into account both benefits and harms of intranasal corticosteroids (INCS), we can consider the following:
Overall, the benefits of INCS seem to outweigh the harms. | ||
Resources requiredHow large are the resource requirements (costs)?" | ||
Judgement | Research evidence | Additional considerations |
Cost of drugs We conducted a survey, having received responses from specialists from 41 countries (mostly in Europe, America and Asia). The yearly across-countries costs are displayed below:  The least expensive and most expensive individual INCS in each country are displayed in the following maps:  Budesonide is often given for free in some low-income countries, as it is in the World Health Organization essential list of medications. Evidence from direct patient data: A preliminary analysis of MASK-air data using the WPAI:AS questionnaire has identified that the overall median work impairment (including both absenteeism and presenteeism) stood at 4.6% (P25-P75: 0.8-15.1%) for well-controlled weeks, ascending to 27.7% (P25-P7512.4-46.0%) and 60.7% (P25-P75: 38.5-80.2%) for partially- and poorly-controlled weeks, respectively. In Germany, this translates into median weekly monetary losses of 42.3 USD PPPs for well-controlled weeks, 259.7 USD PPPs for partially-controlled weeks, and 554.2 USD PPPs for poorly controlled weeks (difference of 511.9 USD per week from poor to good control). For other Western European countries, the difference ranges from 200 to 695 USD. | ||
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Given that intranasal steroids has been around for a long time, there is a reasonably high degree of certainty about the general costs. However, it should be noted that: 1. Available evidence comes from a survey of experts 2. There is substantial difference in costs for specific intranasal corticosteroids (for example mean cost per year of momotasone furoate in Canada range from 102-427$) | ||
Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any cost-effectiveness studies that satisfactorily addressed specific individual intranasal glucocorticosteroid vs. other individual intranasal glucocorticosteroids. Considering the costs reported in the survey alongside differences in VAS EQ-5D assessed using MASK-air data (inverse probability weighting methods were used to account for confounding), fluticasone furoate is cost-effective in relation to fluticasone propionate. Otherwise, mometasone and budesonide tend more frequently to be cost-effective interventions.  | For clarity: Intervention: We consider fluticasone propionate/furoate (based on effectiveness data) Comparison: We consider the others INCS Importantly, cost-effectiveness analysis depend on country-specific costs; in addition, estimates were made based on EQ-5D VAS data (rather than utility data). | |
EquityWhat would be the impact on health equity? | ||
Judgement | Research evidence | Additional considerations |
Availability We conducted a survey, having received responses from specialists from 41 countries (mostly in Europe, America and Asia). The percentage of countries in which each intranasal corticosteroid (INCS) is available for the treatment of allergic rhinitis ranged from 19% to 95%:  Other equity-related aspects  | There are little data available from lower-middle income countries. Budesonide is part of the WHO Essential List of Medicines. The panel discussed that, in some LMIC, medications in this list are given free of charge, (high affordability) but it may not be available (little availability). The panel considered fluticasone propionate/furoate as the "intervention", and budesonide (in the WHO essential list of medicines) and other INCS as the "comparison". It was noted that while budesonide may be more affordable, fluticasone propionate and mometasone may be more available. | |
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
Acceptability We have included 2 studies that provide data on the acceptability of individual intranasal steroids (INCS) (Bachert, Soe). One study was randomized controlled trial (RCT) and 1 evidence synthesis study. Acceptability was measured by drop-outs, compliance and acceptability of sensory attributes. A network meta-analysis [Soe] assessed acceptability of INCS (including mometasone furoate, fluticasone furoate, ciclesonide, fluticasone propionate, and triamcinolone acetonide) through study dropout or discontinuation in RCTs of patients with moderate-severe allergic rhinitis (AR). There was no statistical difference between INCS in both seasonal and perennial AR.  *From Soe, Blue part of the table present results for acceptability Compliance/Satisfaction rate/Sensory attributes Mometasone Furoate (MF) vs fluticasone propionate (FP) For the comparison between mometasone furoate and fluticasone propionate, 4 RCT studies [Stokes 2004, Bunnag 2003, Bachert 2002, Meltzer 2005] showed large heterogeneity among studies with regard to individual attributes. Overall preference for single treatment and compliance is similar for both interventions.  Mometasone furoate (MF) vs. fluticasone furoate (FF) For the comparison between mometasone furoate and fluticasone furoate, two RCT studies [Yanez 2016, Yonezaki 2016] reach opposite conclusions regarding preference. Additionally, there is no consistency between results for individual sensory attributes  Fluticasone furatote (FF) vs fluticasone propionate (FP) We found only one comparative study comparing fluticasone furoate with fluticasone propionate [Meltzer 2010]. More patients (p<0.001) preferred fluticasone furoate to fluticasone propionate based on attributes of scent or odor (58% vs 27%),aftertaste (60% vs 18%), leaking out of the nose and down the throat (59% vs 21%), and mist gentleness (57% vs 26%).  Budesonide (BANS) vs fluticasone propionate (FPNS) For the comparison between budesonide vs fluticasone propionate, we found one study (Shah 2003), that included an analysis of two RCTs. Patients showed a preference for the use of budesonide versus fluticasone propionate. Similar results were observed in terms of overall satisfaction with the sensory features. In the case of single attributes, in both studies, significantly fewer patients perceived scent or taste, forceful spray, and a wet feelin both the nose and throat with budesonide than with fluticasone propionate.  Ciclesonide (CIC) vs. fluticasone propionate (FP) We found only one RCT study comparing ciclesonide with fluticasone propionate [Varshney 2012]. In general, patients significantly preferred fluticasone propionate over ciclesonide overall, and also for the attributes like scent, soothing feel and nasal irritation, sneezing urge.  Triamcinolone acetonide (TAA) vs fluticasone propionate (FP) Based on three RCT studies [Stokes 2004, Bunnag 2003, Bachert 2002] several of the TAA sensory attributes were preferred over those FP. Preference and compliance rate were higher for TAA than FP  Triamcinolone acetonide (TAA) vs mometasone furoate (MF) Based on three RCT studies [Stokes 2004, Bunnag 2003, Bachert 2002] several of the TAA sensory attributes were preferred over those FP. Preference and compliance rate were higher for TAA than FP.  Evidence from direct patient data: In complete weeks of MASK-air reporting during the pollen season, we observed the following percentage of weeks in which each INCS was used for 6 or 7 days:  In the MASK-air dataset, the following information was available for days in which INCS were used and for which patients provided information on how satisfied they were with their treatments (higher values indicating higher satisfaction):  In multivariable mixed-effects models adjusted for the previous day CSMS (a proxy for the severity before taking medication) and for the ARIA score (an indicator of baseline severity), no relevant differences were observed when comparing satisfaction levels between individual intranasal corticosteroids:  In the MASK-air dataset, in 53.0% of the days in which INCS have been used, they have been used in comedication. When considering individual medications, this percentage ranges from 49.3% (mometasone furoate) to 68.1% (budesonide). However, in multivariable mixed-effects models adjusted for the previous day CSMS and for the ARIA score, fluticasone furoate was associated with higher chances of being used in co-medication than budesonide and mometasone, while fluticasone propionate was associated with higher chances of being used in co-medication than budesonide.  Onset of action A rapid review of the literature on the onset of action of specific medications was carried out. The following results were found: 
| The panel noted that all INCS are probably acceptable to key stakeholders (including patients). | |
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify feasibility studies that satisfactorily addressed specific individual intranasal glucocorticosteroid vs. other individual intranasal glucocorticosteroids. | ||
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
There is currently no evidence on the specific impact of individual intranasal corticosteroids on planetary health. Key considerations include the availability of locally produced medications, as well as medication effectiveness in reducing healthcare resource utilization. | The panel noted that the impact on planetary health will depend on the country of manufacturing. Since most INCS are generic, they are made in different countries. In voting, the panel considered mainly the impact of transportation on planetary health. There are differences between countries concerning manufacturing. | |
Summary of judgements
Judgement | |||||||
|---|---|---|---|---|---|---|---|
Problem | No | Probably no | Probably yes | Yes | Varies | Don't know | |
Desirable Effects | Trivial | Small | Moderate | Large | Varies | Don't know | |
Undesirable Effects | Trivial | Small | Moderate | Large | Varies | Don't know | |
Certainty of evidence | Very low | Low | Moderate | High | No included studies | ||
Values | Important uncertainty or variability | Possibly important uncertainty or variability | Probably no important uncertainty or variability | No important uncertainty or variability | |||
Balance of effects | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | Don't know |
Resources required | Large costs | Moderate costs | Negligible costs and savings | Moderate savings | Large savings | Varies | Don't know |
Certainty of evidence of required resources | Very low | Low | Moderate | High | No included studies | ||
Cost effectiveness | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | No included studies |
Equity | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don't know |
Acceptability | No | Probably no | Probably yes | Yes | Varies | Don't know | |
Feasibility | No | Probably no | Probably yes | Yes | Varies | Don't know | |
Planetary health | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don't know |
Type of recommendation
Conclusions
Recommendation |
In patients with allergic rhinitis, the ARIA guideline panel suggests using specific intranasal corticosteroids (in particular, fluticasone furoate or fluticasone propionate) over others (namely, beclomethasone, budesonide, ciclesonide, mometasone and triamcinolone) (conditional recommendation based on mostly very low or low certainty evidence depending on the comparison). |
Justification |
This recommendation is mostly grounded (i) on a favourable balance of effects, and (ii) acceptability of the preferred intranasal corticosteroids. |
Subgroup considerations |
In pre-school and school children, no evidence was available to support a specific recommendation due to insufficient number of primary studies. For patients with asthma, there were no trials specifically comparing patients with and without asthma. However, those trials which included patients with asthma found similar results to those which excluded patients with asthma. RCTs did not present results separately according to sex. |
Implementation considerations |
In low-middle income countries, other individual medications may be preferred based on local availability and affordability (budesonide is the WHO List of Essential Medicines). From a planetary health perspective, locally-produced generics may be preferrable. |
Monitoring and evaluation |
Research priorities |
- Need for studies in specific subgroups of participants or presentation of results by subgroup. Such subgroups include: children and adolescents, older patients, patients with multimorbidity (asthma and conjunctivitis), and patients from ethnic minorities. - Need for studies - particularly randomised controlled trials - evaluating participants with mild allergic rhinitis. - Need for studies evaluating the planetary impact of the interventions. |