Question | |
Should a combination of an intranasal glucocorticosteroid and an intranasal decongestant vs. an intranasal glucocorticosteroid alone be used for the treatment of allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | a combination of an intranasal glucocorticosteroid and an intranasal decongestant |
Comparison: | an intranasal glucocorticosteroid alone |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | |
Background: | Patients with allergic rhinitis using intranasal corticosteroids often do co-medication with intranasal decongestants (oxymetazoline, xylometazoline or tramazoline), particularly as the latter have a fast speed of onset and may help them relieve nasal congestion. |
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 |
Some nasal decongestants (e.g., pseudoephedrine) display safety concerns and have subject of access constraints by the FDA (https://www.fda.gov/drugs/information-drug-class/legal-requirements-sale-and-purchase-drug-products-containing-pseudoephedrine-ephedrine-and). However, nasal decongestants are still largely used in some countries such as Germany (Bousquet et al. Clin Exp Allergy) and xylomethazoline nasal spray in in the WHO essential list of medications ("ear, nose and throat medicines"). 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] References:
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Desirable EffectsHow substantial are the desirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
NOTE: None of the primary studies assessed phenylephrine or pseudoephedrine. The decongestant assessed in included primary studies was oxymetazoline. Nasal symptoms In a systematic review with network meta-analysis performed by Sousa-Pinto et al., we identified scarce evidence on the comparison between combinations of intranasal corticosteroids and nasal decongestants (INCS+DEC) versus intranasal corticosteroids (INCS) on their effect on nasal symptoms. In patients with seasonal allergic rhinitis, two studies computed a total nasal symptom score (TNSS) for comparison of INCS+DEC versus INCS, reaching contradictory results. Meltzer et al. did not identify significant differences between the two interventions (mean change from baseline=-0.36) [1], while the opposite result was obtained by Kumar et al (mean change from baseline=-0.7). However, no further details were provided, precluding meta-analysis [2]. In patients with perennial allergic rhinitis, one study did not identify significant differences in TNSS improvement when comparing fluticasone furoate + oxymetazoline versus fluticasone furoate alone (no further details provided) [3]. Ocular symptoms In a systematic review with network meta-analysis performed by Sousa-Pinto et al., we identified one study performed in patients with seasonal allergic rhinitis and comparing INCS+DEC versus INCS on their effect on the total ocular symptom score (TOSS; combination of three ocular symptoms and scale of 0-9). The study did not find significant differences between fluticasone furoate + oxymetazoline versus fluticasone furoate alone (no further information was provided) [2]. In patients with perennial allergic rhinitis, no primary studies have been found comparing INCS+DEC versus INCS on ocular symptoms. 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+DEC and compared with that registered in patients receiving INCS. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the rhinocojunctivitis quality of life questionnaire (RQLQ; scale of 0-6) results of 32 RCTs (1 RCTs directly assessed INCS+DEC and 19 RCTs directly assessed INCS). INCS+DEC were not associated with a significant difference in RQLQ changes when compared to INCS (mean difference=-0.16; 95%CI=-0.58;0.26). INCS+DEC displayed a 96.5% probability of resulting in a trivial changes when compared to INCS. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 13 RCTs (1 RCTs directly assessed INCS+OAH and 11 RCTs directly assessed INCS). INCS+DEC were not associated with a significant difference in RQLQ changes when compared to INCS (mean difference=0.40; 95%CI=-0.95;1.74). INCS+DEC displayed a 82.3% probability of resulting in a trivial changes when compared to INCS (10.3% probability of resulting in a small meaningful change). Subgroup considerations: Studies including vs. not including patients with 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 were found:  Subgroup considerations: Children and adolescents In a systematic review with network meta-analysis performed by Sousa-Pinto et al., no studies assessing INCS+DEC were available in children. References 1. Meltzer EO, Bernstein DI, Prenner BM, et al. Mometasone furoate nasal spray plus oxymetazoline nasal spray: short-term efficacy and safety in seasonal allergic rhinitis. Am J Rhinol Allergy. 2013;27(2):102-108 2. Kumar RS, Jain MK, Kushwaha JS, et al. Efficacy and Safety of Fluticasone Furoate and Oxymetazoline Nasal Spray: A Novel First Fixed Dose Combination for the Management of Allergic Rhinitis with Nasal Congestion. J Asthma Allergy. 2022;10:15:783-792. 3. Baroody FM, Brown D, Gavanescu L, DeTineo M, Naclerio RM. Oxymetazoline adds to the effectiveness of fluticasone furoate in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol. 2011;127(4):927-934 | ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
NOTE: None of the primary studies assessed phenylephrine or pseudoephedrine. The decongestant assessed in included primary studies was oxymetazoline. The long-term use of nasal decongestants has been linked to rhinitis medicamentosa. Adverse events Following the systematic review performed by Sousa-Pinto et al., the frequency of patients developing at least one adverse event was assessed in patients under intranasal corticosteroids + decongestants (INCS+DEC) and compared with that registered in patients receiving intranasal corticosteroids (INCS). A total of 94 randomised controlled trials (RCTs) reported data on the number of patients with seasonal allergic rhinitis reporting at least one adverse event (1 RCT directly assessed INCS+DEC and 84 RCTs directly assessed INCS). The meta-analytical risk ratio was of 1.79 (95% confidence interval=0.86-3.70) [INCS+DEC was associated with 84 more cases per 1000 patients than INCS; 95%CI = 15 fewer cases to 286 more cases per 1000 patients. Trivial to moderate difference]. A total of 34 RCTs reported data on the number of patients with perennial allergic rhinitis reporting at least one adverse event (1 RCT directly assessed INCS+DEC and 32 RCTs directly assessed INCS). The meta-analytical risk ratio was of 0.61 (95% confidence interval=0.13-2.78) [INCS+DEC was associated with 41 fewer cases per 1000 patients than INCS; 95%CI = 92 fewer cases to 188 more cases per 1000 patients. Trivial to small difference]. Most adverse events which were considered to be related to the treatment were mild and self-limited and comprised headache, epistaxis, nasal discomfort, and upper respiratory tract infection. Subgroup considerations: Studies including vs. not including patients with 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 were found:  Subgroup considerations: Children and adolescents In a systematic review with network meta-analysis performed by Sousa-Pinto et al., no studies assessing INCS+DEC were available in children. Serious adverse events Following the systematic review performed by Sousa-Pinto et al., the frequency of patients developing at least one serious adverse event was assessed both in patients under INCS+DEC and in patients receiving INCS. The following results were observed for seasonal allergic rhinitis:  For patients with perennial allergic rhinitis, the following results were observed:  Subgroup considerations: Children and adolescents In a systematic review with network meta-analysis performed by Sousa-Pinto et al., no studies assessing INCS+DEC were available in children. | ||
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
The certainty of evidence was low for 1 out of 8 analyses, and very low for 7 out of 8 analyses.
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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).  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 + decongestants (INCS+DEC) versus intranasal corticosteroids (INCS), we can consider the following:
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Resources requiredHow large are the resource requirements (costs)?" | ||
Judgement | Research evidence | Additional considerations |
We conducted a survey, having received responses from specialists from 41 countries (mostly in Europe, America and Asia). The costs of being treated for one year with intranasal corticosteroids (INCS) + decongestants (DEC) ranged from 18.0 USD PPP [Bangladesh] to 1190.16 USD PPP [Argentina] (assuming full adherence to treatment and the choice of the least expensive INCS and DEC). This corresponds to weekly costs ranging from 0.4 USD PPP to 22.9 USD PPP. The yearly costs per country are displayed in the following map:  The costs of being treated for one year with INCS ranged from 3.4 US Dollars Power Purchase Parity (PPP) [Israel] to 692.0 USD PPP [Argentina] (assuming full adherence to treatment and the choice of the least expensive INCS). This corresponds to weekly costs ranging from 0.07 USD PPP to 14.4 USD PPP. The yearly costs per country associated with the use of INCS are displayed in the following map:  The differences in costs from adding DEC to INCS in comparison to INCS alone are displayed in the following map:  | ||
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Given that combinations of decongestants and intranasal glucocorticosteroids have been around for a long time, there is a reasonably high degree of certainty about the general costs. It should be noted that available data comes from a survey of experts. | ||
Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that satisfactorily investigated the combination of an intranasal glucocorticosteroid and an intranasal decongestant compared with an intranasal glucocorticosteroid alone in terms of cost effectiveness. | ||
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). Intranasal corticosteroids (INCS) were reported to be available in all assessed countries. All respondents reported availability of at least three different INCS in their respective country. Decongestants (DEC) were reported to be available in 39 out of 41 countries. In 9 countries, only one DEC was available.  Other equity-related aspects  | ||
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
Evidence from MASK-air data Compliance Evidence from direct patient data: In complete weeks of MASK-air reporting during the pollen season, there were 3.4% in which intranasal corticosteroids (INCS) + decongestants (DEC) were used for 6 or 7 days. This compares with 36.0% for INCS. Satisfaction Evidence from direct patient data: In the MASK-air dataset, there were 27 days in which INCS+DEC were used and for which patients provided information on how satisfied they were with their treatments. The median results of the visual analogue scale were of 72 (higher values indicating higher satisfaction) [IQR=19]. In the MASK-air dataset, there were 6239 days in which INCS were used in monotherapy and for which patients provided information on how satisfied they were with their treatments. The median results of the visual analogue scale were of 84 (higher values indicating higher satisfaction) [IQR=31]. | INCS seem to be more acceptable than INCS+DEC | |
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that satisfactorily investigated the combination of an intranasal glucocorticosteroid and an intranasal decongestant compared with an intranasal glucocorticosteroid alone in terms of cost feasibility. However, both intranasal glucocorticosteroids and intranasal decongestants are interventions which have been available for a long time. | Some nasal decongestants have been subject of access constraints by the FDA (https://www.fda.gov/drugs/information-drug-class/legal-requirements-sale-and-purchase-drug-products-containing-pseudoephedrine-ephedrine-and). | |
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that satisfactorily investigated the combination of an intranasal glucocorticosteroid and an intranasal decongestant compared with an intranasal glucocorticosteroid alone in terms of cost planetary health. However, the additional use of intranasal decongestants - compared to the use of intranasal glucocorticosteroids alone - implies the use of additional resources with environmental impact. | ||
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 against using a combination of an intranasal glucocorticosteroid and an intranasal decongestant over an intranasal glucocorticosteroid alone (conditional recommendation based on very low certainty of evidence). |
Justification |
This recommendation is mostly grounded (i) on a unfavourable balance of effects, (ii) moderate costs, and (iii) lower acceptability of the intervention (combination). |
Subgroup considerations |
Recommendation applicable to children and adolescents. |
Implementation considerations |
This recommendation is particularly applicable to long-term treatment (longer than five days). In some specific situations (e.g., low- and middle-income countries where INAH+INCS are not affordable), using intranasal decongestants for a short period of time when INCS are being introduced (so as to “compensate” for the slow onset of action of INCS) can be considered in non-pregnant adults. Evidence based on data on oxymetazoline and xylometazoline for decongestants. Decongestants with limited market access have not been considered. |
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 more well-conducted randomised controlled trials, particularly evaluating participants with perennial allergic rhinitis and those with mild allergic rhinitis. - Need for studies evaluating the cost-effectiveness of the interventions. |