Question | |
Should a combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. an intranasal glucocorticosteroid alone be used for the treatment of allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | a combination of an intranasal H1-antihistamine and an intranasal glucocorticosteroid |
Comparison: | an intranasal glucocorticosteroid alone |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | |
Background: | Intranasal corticosteroids (INCS) + intranasal antihistamines (INAH) offer some advantages in relation to INCS in terms of onset of action and, potentially, effectiveness. However, INCS are more widely available and are more affordable. |
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] 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., nasal symptoms were assessed in patients under fixed combinations of intranasal corticosteroids and H1-antihistamines (INCS+INAH) and compared with that registered in patients receiving intranasal corticosteroids (INCS). For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total nasal symptom score (TNSS; combination of four nasal symptoms and scale of 0-12) results of 78 randomised controlled trials (RCTs). INCS+INAH were associated with a significantly higher improvement in the TNSS when compared to INCS alone (mean difference=-0.30; 95%CI=-0.54;-0.06). INCS+INAH displayed a 7% probability of resulting in a small clinically meaningful improvement when compared to INCS. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 24 RCTs. INCS+INAH were not associated with a significantly higher improvement in the TNSS when compared to INCS alone (mean difference=-0.05; 95%CI=-0.63;0.54). INCS+INAH displayed a 15% probability of resulting in a small clinically meaningful improvement when compared to INCS. 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., for patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the four symptom TNSS results of 9 RCTs. INCS+INAH were not associated with a significant difference compared to INCS on changes to TNSS (mean difference=0.01, 95%CI=-0.56; 0.58). For patients with perennial allergic rhinitis, no studies were available. 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+INAH and compared with that registered in patients receiving INCS. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total ocular symptom score (TOSS; combination of three nasal symptoms and scale of 0-9) results of 54 RCTs. INCS+INAH were associated with a significantly higher improvement in TOSS when compared to INCS (mean difference=-0.21; 95%CI=-0.34;-0.08). INCS+INAH displayed a 0% probability of resulting in a clinically meaningful improvement (100% probability of resulting in a trivial improvement) when compared to INCS. For patients with perennial allergic rhinitis, no RCTs were found. 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., for patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the three symptom TOSS results of 5 RCTs. INCS+INAH were not associated with a significant difference compared to INCS on changes to TNSS (mean difference=-0.25, 95%CI=-0.55; 0.06). For patients with perennial allergic rhinitis, no studies were available. 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+INAH 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 31 RCTs. INCS+INAH were not associated with a significant difference in RQLQ changes when compared to INCS (mean difference=-0.11; 95%CI=-0.23;0.01). INCS+INAH displayed a 4% probability of resulting in a small clinically meaningful improvement (96% probability of resulting in a trivial improvement) when compared to INCS. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 13 RCTs. INCS+INAH were not associated with a significant difference in RQLQ changes when compared to INCS (mean difference=-0.07; 95%CI=-0.45;0.32). INCS+INAH displayed a 7% probability of resulting in a clinically meaningful improvement (93% probability of resulting in a trivial improvement) when compared to INCS. 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., for patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 4 RCTs. INCS+INAH were associated with a significantly higher improvement compared to INCS on changes to RQLQ (mean difference=-0.22; 95%CI=-0.43; -0.01). For patients with perennial allergic rhinitis, no studies were available. | ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
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 + intranasal H1-antihistamines (INCS+INAH) and compared with that registered in patients receiving intranasal corticosteroids (INCS). A total of 75 randomised controlled trials (RCTs) reported data on the number of patients with seasonal allergic rhinitis reporting at least one adverse event. The meta-analytical risk ratio was of 1.67 (95% confidence interval=1.33-2.04) [INCS+INAH was associated with 69 more cases per 1000 patients than INCS; 95%CI = 36 fewer cases to 111 more cases per 1000 patients. Small to Trivial difference]. A total of 30 RCTs reported data on the number of patients with perennial allergic rhinitis reporting at least one adverse event. The meta-analytical risk ratio was of 0.93 (95% confidence interval=0.55-1.59) [INCS+INAH was associated with 19 fewer cases per 1000 patients than INCS; 95%CI = 175 fewer cases to 134 more cases per 1000 patients. Small to Trivial difference] Most adverse events which were considered to be related to the treatment were mild and self-limited and comprised headache, epistaxis, nasal discomfort, upper respiratory tract infection and bitter taste. In an additional analysis of pharmacovigilance data comparing INCS+INAH and INCS, the following results were found:  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 performed by Sousa-Pinto et al., a total of 11 RCTs reported data on the number of patients with seasonal allergic rhinitis reporting at least one adverse event. The meta-analytical risk ratio was of 1.12 (95%CI=0.70; 1.78) [INCS+INAH was associated with 13 more cases per 1000 individuals than INCS; from 32 fewer cases to 83 more cases per 1000 individuals. Trivial difference]. For patients with perennial allergic rhinitis, no studies were available. 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+INAH and in patients receiving INCS. The following results were observed for seasonal allergic rhinitis:  The following results were observed for perennial allergic rhinitis:  In an additional analysis of pharmacovigilance data, important adverse events were 1.9 times (95%CI = 1.5; 2.2) more common with INCS than with INCS+INAH. Subgroup considerations: Children and adolescents In a systematic review performed by Sousa-Pinto et al., 0 serious adverse events were registered in 398 children with seasonal allergic rhinitis treated with INAH+INCS.. This compares to 4 serious adverse events registered in 2012 children treated with INCS. No evidence on the frequency of serious AE in children with perennial allergic rhinitis treated with INAH+INCS. This compares to 11 serious adverse events registered in 2985 children treated with INCS. | Potential considerations regarding somnolence and its differential impact on particular professions. Taking into account the differential side effects in each combinations - epistaxis for INCS; bitter taste for combinations. | |
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
The certainty of evidence was moderate for 3 out of 9 analyses, high for 2 out of 9 analyses, and very low for 4 out of 9 analyses.
| Moderate for SAR Very low for PAR (considering, among others the lack of evidence for one of the interventions) | |
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 + intranasal H1-antihistamines (INCS+INAH) 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). In 36 of these countries, both intranasal corticosteroids (INCS) and INCS+ intranasal antihistamines (INAH) were available. 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 costs of being treated for one year with INCS+INAH ranged from 32.4 US Dollars Power Purchase Parity (PPP) [Bangladesh] to 1209.0 USD PPP [Argentina] (assuming full adherence to treatment and the choice of the least expensive INAH). This corresponds to weekly costs ranging from 0.62 USD PPP to 23.3 USD PPP. The yearly costs per country associated with the use of INCS+INAH are displayed in the following map:  In 34 out of the 36 countries where both INCS+INAH and INCS were reported to be available, INCS+INAH were associated with higher costs than INCS:  Evidence from direct patient data: An 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 3.1% (90% CrI: 0.0-28.6%) for well-controlled weeks, ascending to 25.6% (90% CrI: 0.0-65.9%) and 65.4% (90% CrI: 36.6-93.7%) for partially- and poorly-controlled weeks, respectively. In Germany, this translates into median weekly monetary losses of 24.0 USD PPPs for well-controlled weeks, 196.7 USD PPPs for partially-controlled weeks, and 555.4 USD PPPs for poorly controlled weeks (difference of 531.4 USD per week from poor to good control). For other Western European countries, the difference ranges from 262 to 490 USD. | Moving target - e.g., decrease in costs with generic formulations. | |
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 intranasal steroids and antihistamines and intranasal steroids alone and 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 interventions | ||
Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
No published cost utility or cost-effectiveness analyses for nasal corticosteroids were identified in the literature databases. However, through a supplementary search conducted on the INAHTA database and the HTA agency website, one reimbursement recommendation (specifically for Azelastine/Fluticasone) was found on the CADTH website, which included cost-effectiveness data for the comparison Dymista versus fluticasone. The manufacturer’s economic submission for drug Dymista reported that, based on a cost-utility analysis, ICUR was $70,957 per QALY. The manufacturer's submission had several limitations, that were noted in CDR PHARMACOECONOMIC REVIEW REPORT such as the source of input data (efficacy data), the time horizon of the analysis, the assessment of adverse events' impact on quality of life, and adjustments of Quality-Adjusted Life Years (QALY). Based on The CDR multi-way reanalysis ICUR of AZE/FP vs. FP was $194,592 per QALY. Considering the costs reported in the survey alongside the differences in QALYs reported in the CDR Pharmacoeconomic Review Report, INCS would be dominated by INCS+INAH in 2 out of 36 countries (more expensive and associated with lower gains QALYs; assumption of full adherence to treatment and the choice of the least expensive medication of each class). In all remaining countries except three (Argentina, Canada and Colombia), INCS+INAH would be cost-effective at a willingness to pay threshold of $50,000/QALY gained. Considering the conservative willingness to pay threshold of 1 time the GDP per capita, INCS+INAH would only not be cost-effective in nine countries (Argentina, Brazil, Canada, Colombia, India, Kazakhstan, Paraguay, Syria and Vietnam). INCS+INAH would be cost-effective in all assessed countries (considering both the willingness-to-pay threshold of $50,000/QALY gained or that of 1 time the GDP per capita) if considering differences in VAS EQ-5D assessed using MASK-air data (inverse probability weighting methods were used to account for confounding). | Probably cost-effectiveness depends on the severity of the patients. In patients with more severe disease, it is expected that fixed combinations are more cost-effective on account of the decrease of healthcare resources and increase of work productivity. | |
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. INCS + intranasal antihistamines (INCS+INAH) were reported to be available in 36 out of 41 countries. In 22 countries, only one INCS+INAH was available.  Other equity-related aspects  | ||
AcceptabilityIs the intervention acceptable to key interest-holders? | ||
Judgement | Research evidence | Additional considerations |
We found one study [Fairchild] that provides data on the acceptability of intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. an intranasal glucocorticosteroid alone. Both studies has veen conducted in North America or Europe. Additional evidence comes from direct patient data (MASK-AIR). Compliance Evidence from direct patient data: In complete weeks of MASK-air reporting during the pollen season, there were 31.7% in which INCS+INAH were used for 6 or 7 days. This compares with 36.0% for INCS. Evidence from direct patient data: In the MASK-air dataset, there were 2834 days in which INAH+INCS (fixed combinations) 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 83 (higher values indicating higher satisfaction) [IQR=24]. There were 6174 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 86 (higher values indicating higher satisfaction) [IQR=26]. In multivariable linear regression models adjusted for the CSMS of the previous day (a proxy variable of the rhinitis control level before medication use) and for the patients’ ARIA score (an indicator of disease severity), INAH+INCS were associated with higher VAS satisfaction than INCS (average difference: 0.39; 95%CI=-1.08;1.86). Switching rate Unsatisfactory treatment indication (augmentation with a prescription oral antihistamine or another intranasal therapy) occurred in 35,24% of patients in combined INAH+INCS cohort in comparison to the 27.64% in the INCS [Fairchild] Evidence from direct patient data: In the MASK-air dataset, in 56.2% of the days in which INCS have been used, they have been used in comedication. This compares with 51.0% for the fixed combination of INCS+INAH. Compared to other rhinitis medication classes, INCS was associated with lower odds of being used in co-medication (OR=0.90; 95%CI=0.86-0.93) in a study using multivariable mixed-effects logistic regression models [Sousa-Pinto]. The same study found that INAH+INCS (OR=0.75; 95%CI=0.71-0.80) were also associated with lower odds of being used in co-medication. In multivariable linear regression models adjusted for the CSMS of the previous day (a proxy variable of the rhinitis control level before medication use) and for the patients’ ARIA score (an indicator of disease severity), INCS were associated with higher odds of being used of co-medication than INAH+INCS (OR=1.27; 95%CI=0.91;1.77). Onset of action A rapid review of the literature on the onset of action of intranasal corticosteroids + intranasal antihistamines and intranasal corticosteroids was carried out. The following results were found:  References: 1. Fairchild CJ, Durden E, Cao Z, Smale P. Outcomes and cost comparison of three therapeutic approaches to allergic rhinitis. Am J Rhinol Allergy. 2011 Jul-Aug;25(4):257-62. doi: 10.2500/ajra.2011.25.3636. Epub 2011 May 31. PMID: 21639996. | ||
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any feasibility studies that satisfactorily addressed comparison of intranasal H1-antihistamine and an intranasal glucocorticosteroid vs. an intranasal glucocorticosteroid alone. | ||
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
There is currently no evidence on the comparative impact of intranasal glucocorticosteroids and intranasal H1-antihistamines versus intranasal glucocorticosteroids on planetary health. Key considerations include the availability of locally produced medications, as well as medication effectiveness in reducing healthcare resource utilization. | There was some uncertainty on the judgement. Aspects related to the transportation were taken into account as potentially important. Some members referred that possibly the impact is not large. | |
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 a fixed combination of an intranasal antihistamine and an intranasal glucocorticosteroid over an intranasal corticosteroid alone (conditional recommendation based on moderate certainty of evidence for seasonal allergic rhinitis and on very low certainty of evidence for perennial allergic rhinitis). |
Justification |
This recommendation is mostly grounded on acceptability and cost-effectiveness data. |
Subgroup considerations |
Considerations for children and adolescents: This recommendation is also applicable to children and adolescents. In the subgroup of children and adolescents, INCS+INAH were not associated with a significant difference compared to INCS alone on changes to TNSS or TOSS in patients with seasonal allergic rhinitis. On the other hand, a significantly higher improvement in RQLQ was observed. For patients with perennial allergic rhinitis no studies were available. The subgroup analysis of the network meta-analysis performed by Sousa-Pinto et al., grouping trials according to whether they had excluded patients with asthma, INCS+INAH vs INCS showed a significant improvement in TNSS and TOSS in the subgroup of seasonal allergic rhinitis patients without asthma but not in the subgroup which included them. The opposite was observed for RQLQ, with results showing a significant improvement only when all seasonal allergic rhinitis patients were considered but not when asthma patients were excluded. Only 5 RCTs on the comparison of INCS+INAH vs INCS alone assessed patients with perennial allergic rhinitis and the only outcome measured was the TNSS for which no significant difference was observed. The probability of a relevant clinical improvement did not reach 50% for any assessed outcomes. |
Implementation considerations |
This EtD reflects average class effects. Aspects such as adherence, baseline severity and history of medication use may be relevant to be considered. Fixed combinations of INAH+INCS may be particularly favoured in patients with severe symptoms. In low-income countries or low-resource settings, INCS may be preferred. |
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 (perennial allergic rhinitis), 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 health impact of the interventions. |